Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor alpha production of monocytes .

Mechanism of the inhibitory effect of protease inhibitor on <protein>tumor necrosis factor alpha</protein> production of <cell_type>monocytes</cell_type> .


If the inflammatory response becomes excessive or uncontrolled by some stimuli , inappropriate inflammatory responses occur .


Monocytes are extremely important cells for regulating the cytokine network and tumor necrosis factor alpha ( TNFalpha ) and interleukin- ( IL ) 10 , which are mainly synthesized by monocytes , are representative cytokines that play a central role in the cytokine network .

<cell_type>Monocytes</cell_type> are extremely important cells for regulating the cytokine network and <protein>tumor necrosis factor alpha</protein> ( <protein>TNFalpha</protein> ) and <protein>interleukin- ( IL ) 10</protein> , which are mainly synthesized by <cell_type>monocytes</cell_type> , are representative <protein>cytokines</protein> that play a central role in the cytokine network .


Protease inhibitors such as gabexate mesilate ( GM ) and ulinastatin ( UTI ) have been shown to have various beneficial effects by inhibiting the activation of leukocytes , but the mechanism for this has yet to be fully elucidated .

Protease inhibitors such as gabexate mesilate ( GM ) and ulinastatin ( UTI ) have been shown to have various beneficial effects by inhibiting the activation of <cell_type>leukocytes</cell_type> , but the mechanism for this has yet to be fully elucidated .


In this study we investigated the mechanism of the inhibitory effect of protease inhibitors on the proinflammatory cytokine production of lipopolysaccharide- ( LPS ) stimulated monocytes .

In this study we investigated the mechanism of the inhibitory effect of protease inhibitors on the proinflammatory cytokine production of lipopolysaccharide- ( LPS ) stimulated <cell_type>monocytes</cell_type> .


LPS-stimulated monocytes were treated with GM or UTI .

LPS-stimulated <cell_type>monocytes</cell_type> were treated with GM or UTI .


The value of TNFalpha and IL-10 in the culture medium of monocytes was measured and each mRNA expression was assayed .

The value of <protein>TNFalpha</protein> and <protein>IL-10</protein> in the culture medium of <cell_type>monocytes</cell_type> was measured and each mRNA expression was assayed .


The inhibitory effect of protease inhibitors on the activity of intracellular signal transduction pathways such as protein kinase C ( PKC ) and nuclear factor kappa B ( NFkappaB ) were also evaluated .

The inhibitory effect of protease inhibitors on the activity of intracellular signal transduction pathways such as <protein>protein kinase C</protein> ( <protein>PKC</protein> ) and <protein>nuclear factor kappa B</protein> ( <protein>NFkappaB</protein> ) were also evaluated .


GM decreased the TNFalpha production of LPS-stimulated monocytes as shown by the inhibition of mRNA expression and increased the IL-10 production of LPS-stimulated monocytes .

GM decreased the <protein>TNFalpha</protein> production of LPS-stimulated <cell_type>monocytes</cell_type> as shown by the inhibition of mRNA expression and increased the <protein>IL-10</protein> production of LPS-stimulated <cell_type>monocytes</cell_type> .


GM also suppressed the NFkappaB activity of LPS-stimulated monocytes .

GM also suppressed the <protein>NFkappaB</protein> activity of LPS-stimulated <cell_type>monocytes</cell_type> .


UTI decreased the TNFalpha production of LPS-stimulated monocytes , but did not inhibit the TNFalpha mRNA expression .

UTI decreased the <protein>TNFalpha</protein> production of LPS-stimulated <cell_type>monocytes</cell_type> , but did not inhibit the <rna>TNFalpha mRNA</rna> expression .


The present study shows that the inhibitory effect of GM on the TNFalpha production of activated human monocytes is mediated by the suppression of NFkappaB activation , while the mechanism of UTI inhibiting TNFalpha production of human monocytes may be due to the inhibition of either the translation or secretion of TNFalpha .

The present study shows that the inhibitory effect of GM on the <protein>TNFalpha</protein> production of activated <cell_type>human monocytes</cell_type> is mediated by the suppression of <protein>NFkappaB</protein> activation , while the mechanism of UTI inhibiting <protein>TNFalpha</protein> production of <cell_type>human monocytes</cell_type> may be due to the inhibition of either the translation or secretion of <protein>TNFalpha</protein> .


Homocysteine stimulates the expression of monocyte chemoattractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis .

Homocysteine stimulates the expression of <protein>monocyte chemoattractant protein-1</protein> in <cell_type>endothelial cells</cell_type> leading to enhanced monocyte chemotaxis .


Hyperhomocysteinemia has been identified as an independent risk factor for atherosclerosis .


The infiltration of monocytes into the arterial wall is one of the key events during atherogenesis .

The infiltration of <cell_type>monocytes</cell_type> into the arterial wall is one of the key events during atherogenesis .


Monocyte chemoattractant protein-1 ( MCP-1 ) is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall .

<protein>Monocyte chemoattractant protein-1</protein> ( <protein>MCP-1</protein> ) is a potent <protein>chemokine</protein> that stimulates the migration of <cell_type>monocytes</cell_type> into the intima of the arterial wall .


The mechanism by which increased monocyte infiltration occurs in atherosclerotic lesions in patients with hyperhomocysteinemia has not been delineated .


The objective of the present study was to investigate the effect of homocysteine on MCP-1 production in endothelial cells .

The objective of the present study was to investigate the effect of homocysteine on <protein>MCP-1</protein> production in <cell_type>endothelial cells</cell_type> .


Cells were incubated with homocysteine .


The secretion of MCP-1 protein was significantly increased ( 195 % as compared to the control ) in cells treated with pathological concentrations of homocysteine .

The secretion of <protein>MCP-1 protein</protein> was significantly increased ( 195 % as compared to the control ) in cells treated with pathological concentrations of homocysteine .


Such effect was accompanied by an increased expression of MCP-1 mRNA ( 176 % as compared to the control ) in endothelial cells which resulted in enhanced monocyte chemotaxis .

Such effect was accompanied by an increased expression of <rna>MCP-1 mRNA</rna> ( 176 % as compared to the control ) in <cell_type>endothelial cells</cell_type> which resulted in enhanced monocyte chemotaxis .


The p38 MAP kinase as well as other members of the p38 MAP kinase pathway , including MKK3 , MKK6 , ATF-2 and Elk-1 , were activated in homocysteine-treated cells .

The <protein>p38 MAP kinase</protein> as well as other members of the p38 MAP kinase pathway , including <protein>MKK3</protein> , <protein>MKK6</protein> , <protein>ATF-2</protein> and <protein>Elk-1</protein> , were activated in <cell_type>homocysteine-treated cells</cell_type> .


Homocysteine-induced MCP-1 expression and subsequent monocyte chemotaxis were blocked by a p38 MAP kinase inhibitor ( SB203580 ) suggesting that the p38 MAP kinase pathway might be involved in homocysteine-induced MCP-1 expression in endothelial cells .

Homocysteine-induced <protein>MCP-1</protein> expression and subsequent monocyte chemotaxis were blocked by a <protein>p38 MAP kinase</protein> inhibitor ( SB203580 ) suggesting that the <protein>p38 MAP kinase</protein> pathway might be involved in homocysteine-induced <protein>MCP-1</protein> expression in <cell_type>endothelial cells</cell_type> .


In contrast , staurosporine , a protein kinase C inhibitor , had no effect on homocysteine-induced MCP-1 expression .

In contrast , staurosporine , a <protein>protein kinase C</protein> inhibitor , had no effect on homocysteine-induced <protein>MCP-1</protein> expression .


In conclusion , our results indicate that homocysteine stimulates MCP-1 expression in endothelial cells leading to enhanced monocyte chemotaxis .

In conclusion , our results indicate that homocysteine stimulates <protein>MCP-1</protein> expression in <cell_type>endothelial cells</cell_type> leading to enhanced monocyte chemotaxis .


Inducible resistance to Fas-mediated apoptosis in B cells .

Inducible resistance to Fas-mediated apoptosis in <cell_type>B cells</cell_type> .


Apoptosis produced in B cells through Fas ( APO-1 , CD95 ) triggering is regulated by signals derived from other surface receptors : CD40 engagement produces upregulation of Fas expression and marked susceptibility to Fas -induced cell death , whereas antigen receptor engagement , or IL-4R engagement , inhibits Fas killing and in so doing induces a state of Fas -resistance , even in otherwise sensitive , CD40 -stimulated targets .

Apoptosis produced in <cell_type>B cells</cell_type> through <protein>Fas</protein> ( <protein>APO-1</protein> , <protein>CD95</protein> ) triggering is regulated by signals derived from other surface receptors : CD40 engagement produces upregulation of <protein>Fas</protein> expression and marked susceptibility to <protein>Fas</protein> -induced cell death , whereas antigen receptor engagement , or IL-4R engagement , inhibits <protein>Fas</protein> killing and in so doing induces a state of <protein>Fas</protein> -resistance , even in otherwise sensitive , <protein>CD40</protein> -stimulated targets .


Surface immunoglobulin and IL-4R utilize at least partially distinct pathways to produce Fas -resistance that differentially depend on PKC and STAT6 , respectively .

<protein>Surface immunoglobulin</protein> and <protein>IL-4R</protein> utilize at least partially distinct pathways to produce <protein>Fas</protein> -resistance that differentially depend on <protein>PKC</protein> and <protein>STAT6</protein> , respectively .


Further , surface immunoglobulin signaling for inducible Fas -resistance bypasses Btk , requires NF-kappaB , and entails new macromolecular synthesis .

Further , surface immunoglobulin signaling for inducible <protein>Fas</protein> -resistance bypasses <protein>Btk</protein> , requires <protein>NF-kappaB</protein> , and entails new macromolecular synthesis .


Terminal effectors of B cell Fas -resistance include the known anti-apoptotic gene products , Bcl-xL and FLIP , and a novel anti-apoptotic gene that encodes FAIM ( Fas Apoptosis Inhibitory Molecule ) .

Terminal effectors of <cell_type>B cell</cell_type> <protein>Fas</protein> -resistance include the known <protein>anti-apoptotic gene products</protein> , <protein>Bcl-xL</protein> and <protein>FLIP</protein> , and a novel <dna>anti-apoptotic gene</dna> that encodes <protein>FAIM</protein> ( <protein>Fas Apoptosis Inhibitory Molecule</protein> ) .


faim was identified by differential display and exists in two alternatively spliced forms ; faim-S is broadly expressed , but faim-L expression is tissue-specific .

<protein>faim</protein> was identified by differential display and exists in two alternatively spliced forms ; <protein>faim-S</protein> is broadly expressed , but faim-L expression is tissue-specific .


The FAIM sequence is highly evolu- tionarily conserved , suggesting an important role for this molecule throughout phylogeny .

The <dna>FAIM sequence</dna> is highly evolu- tionarily conserved , suggesting an important role for this molecule throughout phylogeny .


Inducible resistance to Fas killing is hypothesized to protect foreign antigen-specific B cells during potentially hazardous interactions with FasL-bearing T cells , whereas autoreactive B cells fail to become Fas -resistant and are deleted via Fas -dependent cytotoxicity .

Inducible resistance to <protein>Fas</protein> killing is hypothesized to protect foreign antigen-specific <cell_type>B cells</cell_type> during potentially hazardous interactions with <cell_type>FasL-bearing T cells</cell_type> , whereas <cell_type>autoreactive B cells</cell_type> fail to become <protein>Fas</protein> -resistant and are deleted via <protein>Fas</protein> -dependent cytotoxicity .


Inadvertent or aberrant acquisition of Fas -resistance may permit autoreactive B cells to escape Fas deletion , and malignant lymphocytes to impede anti-tumor immunity .

Inadvertent or aberrant acquisition of <protein>Fas</protein> -resistance may permit <cell_type>autoreactive B cells</cell_type> to escape <protein>Fas</protein> deletion , and <cell_type>malignant lymphocytes</cell_type> to impede anti-tumor immunity .


Stromal cell-derived factor 1 alpha -induced chemotaxis in T cells is mediated by nitric oxide signaling pathways .

<protein>Stromal cell-derived factor 1 alpha</protein> -induced chemotaxis in <cell_type>T cells</cell_type> is mediated by nitric oxide signaling pathways .


Stromal cell-derived factor 1 alpha ( SDF1 alpha ) and its cognate chemokine receptor CXCR4 act as potent chemoattractants and regulate trafficking and homing of hematopoietic progenitor cells and lymphocytes .

<protein>Stromal cell-derived factor 1 alpha</protein> ( <protein>SDF1 alpha</protein> ) and its cognate <protein>chemokine receptor CXCR4</protein> act as potent chemoattractants and regulate trafficking and homing of <cell_type>hematopoietic progenitor cells</cell_type> and <cell_type>lymphocytes</cell_type> .


However , the molecular mechanisms regulating SDF1 alpha -driven cell migration are not well defined .

However , the molecular mechanisms regulating <protein>SDF1 alpha</protein> -driven cell migration are not well defined .


In this study , we have explored the roles of the second messenger NO and the transcription factor NF-kappa B in SDF1 alpha -induced T cell migration .

In this study , we have explored the roles of the second messenger NO and the <protein>transcription factor NF-kappa B</protein> in <protein>SDF1 alpha</protein> -induced T cell migration .


SDF1 alpha treatment of Jurkat T cells increased the activity of NO synthase , which catalyzes the generation of NO .

<protein>SDF1 alpha</protein> treatment of <cell_line>Jurkat T cells</cell_line> increased the activity of <protein>NO synthase</protein> , which catalyzes the generation of NO .


We observed that pretreatment of Jurkat cells or activated PBLs with several NO donors significantly enhanced the SDF1 alpha -induced migration , whereas various inhibitors of NO synthase markedly abrogated the chemotactic response in a concentration-dependent manner .

We observed that pretreatment of <cell_line>Jurkat cells</cell_line> or activated <cell_type>PBLs</cell_type> with several NO donors significantly enhanced the <protein>SDF1 alpha</protein> -induced migration , whereas various inhibitors of <protein>NO synthase</protein> markedly abrogated the chemotactic response in a concentration-dependent manner .


Furthermore , we observed that inhibitors of the transcription factor NF-kappa B , which is linked to NO signaling pathways , also significantly blocked the SDF1 alpha -induced chemotactic response .

Furthermore , we observed that inhibitors of the <protein>transcription factor NF-kappa B</protein> , which is linked to NO signaling pathways , also significantly blocked the <protein>SDF1 alpha</protein> -induced chemotactic response .


However , these compounds did not have a significant effect on SDF1 alpha -induced mitogen-activated protein kinase activity .

However , these compounds did not have a significant effect on <protein>SDF1 alpha</protein> -induced mitogen-activated protein kinase activity .


In addition , the MAP/Erk kinase kinase inhibitor PD98059 did not abrogate SDF1 alpha -induced chemotaxis .

In addition , the MAP/Erk kinase kinase inhibitor PD98059 did not abrogate <protein>SDF1 alpha</protein> -induced chemotaxis .


AKT , which has been shown to mediate NO production , was also phosphorylated upon SDF1 alpha stimulation .

<protein>AKT</protein> , which has been shown to mediate NO production , was also phosphorylated upon <protein>SDF1 alpha</protein> stimulation .


These studies suggest that NO-related signaling pathways may mediate SDF1 alpha -induced chemotaxis , but not mitogen-activated protein kinase activation .

These studies suggest that NO-related signaling pathways may mediate <protein>SDF1 alpha</protein> -induced chemotaxis , but not <protein>mitogen-activated protein kinase</protein> activation .


The lack of NF-kappa B transactivation and PKC epsilon expression in CD4 ( + ) CD8 ( + ) thymocytes correlates with negative selection .

The lack of NF-kappa B transactivation and PKC epsilon expression in <cell_type>CD4 ( + ) CD8 ( + ) thymocytes</cell_type> correlates with negative selection .


Deletion of autoreactive thymocytes at the DP stage is the basis for tolerance to thymus-expressed self antigens .

Deletion of <cell_type>autoreactive thymocytes</cell_type> at the DP stage is the basis for tolerance to <protein>thymus-expressed self antigens</protein> .


In this study we investigated whether distinct signalling pathways are induced in DP thymocytes as compared to mature T cells upon stimulation with antigen .

In this study we investigated whether distinct signalling pathways are induced in <cell_type>DP thymocytes</cell_type> as compared to <cell_type>mature T cells</cell_type> upon stimulation with antigen .


Using triple transgenic mice expressing a TCR transgene , dominant negative ras/Mek proteins and a reporter gene construct with AP-1 or NF-kappa B binding sites , we showed a complete lack of transcriptional activity of NF-kappa B but not AP-1 in DP thymocytes , whereas both were transcriptionally active in mature T cells after antigenic stimulation .

Using triple transgenic mice expressing a <dna>TCR transgene</dna> , <protein>dominant negative ras/Mek proteins</protein> and a <dna>reporter gene construct</dna> with <dna>AP-1 or NF-kappa B binding sites</dna> , we showed a complete lack of transcriptional activity of <protein>NF-kappa B</protein> but not <protein>AP-1</protein> in <cell_type>DP thymocytes</cell_type> , whereas both were transcriptionally active in <cell_type>mature T cells</cell_type> after antigenic stimulation .


Lack of NF-kappa B induction correlated with increased death in response to antigen .

Lack of <protein>NF-kappa B</protein> induction correlated with increased death in response to <protein>antigen</protein> .


AP-1 induction was dependent on the integrity of the ras/Mek pathway indicating that this pathway was activated in the DP thymocytes .

<protein>AP-1</protein> induction was dependent on the integrity of the ras/Mek pathway indicating that this pathway was activated in the <cell_type>DP thymocytes</cell_type> .


In contrast , we found a complete lack of constitutive expression of the epsilon isoform of Protein Kinase C ( PKC ) in DP thymocytes , although it was present in mature thymocytes and peripheral T cells .

In contrast , we found a complete lack of constitutive expression of the <protein>epsilon isoform of Protein Kinase C</protein> ( <protein>PKC</protein> ) in <cell_type>DP thymocytes</cell_type> , although it was present in <cell_type>mature thymocytes</cell_type> and <cell_type>peripheral T cells</cell_type> .


Taken together the results suggest that the lack of PKC epsilon in DP thymocytes could lead to the absence of NF-kappa B activity after antigenic stimulation contributing to negative selection .

Taken together the results suggest that the lack of <protein>PKC epsilon</protein> in <cell_type>DP thymocytes</cell_type> could lead to the absence of <protein>NF-kappa B</protein> activity after antigenic stimulation contributing to negative selection .


Cell Death and Differentiation ( 2000 ) 7 , 1253 - 1262 .


CD2 stimulation leads to the delayed and prolonged activation of STAT1 in T cells but not NK cells .

CD2 stimulation leads to the delayed and prolonged activation of <protein>STAT1</protein> in <cell_type>T cells</cell_type> but not <cell_type>NK cells</cell_type> .


OBJECTIVE : T lymphocytes can be activated by soluble factors such as cytokines or through direct cell-cell interactions .

OBJECTIVE : <cell_type>T lymphocytes</cell_type> can be activated by soluble factors such as <protein>cytokines</protein> or through direct cell-cell interactions .


Although cytokine receptors are known to signal through STAT family transcription factors , the mechanisms by which other cell-surface molecules , such as CD2 , transduce signals is unclear .

Although <protein>cytokine receptors</protein> are known to signal through <protein>STAT family transcription factors</protein> , the mechanisms by which other <protein>cell-surface molecules</protein> , such as <protein>CD2</protein> , transduce signals is unclear .


The goal of this study was to determine whether stimulation of T cells through CD2 recapitulates aspects of cytokine -induced T-cell activation by use of STAT transcription factors .

The goal of this study was to determine whether stimulation of <cell_type>T cells</cell_type> through <protein>CD2</protein> recapitulates aspects of <protein>cytokine</protein> -induced T-cell activation by use of <protein>STAT transcription factors</protein> .


MATERIALS AND METHODS : T cells were treated with anti-CD2 antibodies or cells bearing the natural CD2 ligand CD58 , after which signaling through STAT transcription factors was assessed .

MATERIALS AND METHODS : <cell_type>T cells</cell_type> were treated with <protein>anti-CD2 antibodies</protein> or cells bearing the natural <protein>CD2 ligand CD58</protein> , after which signaling through <protein>STAT transcription factors</protein> was assessed .


RESULTS : Stimulation of CD2 on primary T lymphocytes leads to the tyrosine phosphorylation , nuclear translocation , and DNA binding of STAT1 .

RESULTS : Stimulation of <protein>CD2</protein> on <cell_type>primary T lymphocytes</cell_type> leads to the tyrosine phosphorylation , nuclear translocation , and DNA binding of <protein>STAT1</protein> .


In contrast to stimulation by cytokines , the activation of STAT1 in response to CD2 ligation is delayed and does not involve Jak kinases .

In contrast to stimulation by <protein>cytokines</protein> , the activation of <protein>STAT1</protein> in response to CD2 ligation is delayed and does not involve <protein>Jak kinases</protein> .


Furthermore , while STAT phosphorylation induced by cytokines is generally transient , STAT1 phosphorylation following CD2 stimulation persists for a period of days .

Furthermore , while STAT phosphorylation induced by <protein>cytokines</protein> is generally transient , STAT1 phosphorylation following CD2 stimulation persists for a period of days .


Transcription of key target genes such as IRF1 and c-fos proceeds with delayed kinetics following CD2 stimulation , suggesting that this unique pattern of STAT activation may lead to a distinct cellular response following CD2 ligation .

Transcription of key target genes such as <dna>IRF1</dna> and <dna>c-fos</dna> proceeds with delayed kinetics following CD2 stimulation , suggesting that this unique pattern of STAT activation may lead to a distinct cellular response following CD2 ligation .


This pathway appears to be restricted to T cells , as stimulation of CD2 on NK cells does not lead to STAT1 activation .

This pathway appears to be restricted to <cell_type>T cells</cell_type> , as stimulation of <protein>CD2</protein> on <cell_type>NK cells</cell_type> does not lead to STAT1 activation .


CONCLUSION : Stimulation of T cells through cell-surface molecules such as CD2 involves activation of STAT transcription factors , thus recapitulating elements of cytokine signaling .

CONCLUSION : Stimulation of <cell_type>T cells</cell_type> through <protein>cell-surface molecules</protein> such as <protein>CD2</protein> involves activation of <protein>STAT transcription factors</protein> , thus recapitulating elements of cytokine signaling .


NFATc1 and NFATc2 together control both T and B cell activation and differentiation .

<protein>NFATc1</protein> and <protein>NFATc2</protein> together control both T and B cell activation and differentiation .


NFAT transcription factors play critical roles in gene transcription during immune responses .

<protein>NFAT transcription factors</protein> play critical roles in gene transcription during immune responses .


To investigate further the two most prominent NFAT family members , NFATc1 and NFATc2 , we generated mice bearing lymphoid systems devoid of both .

To investigate further the two most prominent <protein>NFAT family members</protein> , <protein>NFATc1</protein> and <protein>NFATc2</protein> , we generated mice bearing lymphoid systems devoid of both .


Doubly deficient T cells displayed cell surface markers of activation yet were significantly deficient in the development of multiple effector functions , including Th cytokine production , surface effector molecule expression , and cytolytic activity .

Doubly deficient <cell_type>T cells</cell_type> displayed cell surface markers of activation yet were significantly deficient in the development of multiple effector functions , including <protein>Th cytokine</protein> production , <protein>surface effector molecule</protein> expression , and cytolytic activity .


Nevertheless , doubly deficient B cells were hyperactivated , as evidenced by extremely elevated serum IgG1 and IgE , as well as plasma cell expansion and infiltration of end organs .

Nevertheless , <cell_type>doubly deficient B cells</cell_type> were hyperactivated , as evidenced by extremely elevated serum <protein>IgG1</protein> and <protein>IgE</protein> , as well as <cell_type>plasma cell</cell_type> expansion and infiltration of end organs .


Thus , in T cells , NFATc1 and NFATc2 are dispensable for inflammatory reactivity but are required for effector differentiation , while in B cells , NFATs regulate both normal homeostasis and differentiation .

Thus , in <cell_type>T cells</cell_type> , <protein>NFATc1</protein> and <protein>NFATc2</protein> are dispensable for inflammatory reactivity but are required for effector differentiation , while in <cell_type>B cells</cell_type> , <protein>NFATs</protein> regulate both normal homeostasis and differentiation .


Epstein-barr virus immediate-early protein BZLF1 is SUMO-1 modified and disrupts promyelocytic leukemia bodies .

Epstein-barr virus <protein>immediate-early protein BZLF1</protein> is SUMO-1 modified and disrupts promyelocytic leukemia bodies .


Although the immediate-early proteins of both herpes simplex virus ( HSV ) and cytomegalovirus ( CMV ) are known to modify promyelocytic leukemia ( PML ) ( ND10 ) bodies in the nucleus of the host cell , it has been unclear whether lytic infection with gamma herpesviruses induces a similar effect .

Although the <protein>immediate-early proteins</protein> of both herpes simplex virus ( HSV ) and cytomegalovirus ( CMV ) are known to modify promyelocytic leukemia ( PML ) ( ND10 ) bodies in the nucleus of the host cell , it has been unclear whether lytic infection with gamma herpesviruses induces a similar effect .


The PML protein is induced by interferon , involved in major histocompatibility complex class I presentation , and necessary for certain types of apoptosis .

The <protein>PML protein</protein> is induced by <protein>interferon</protein> , involved in <protein>major histocompatibility complex class I</protein> presentation , and necessary for certain types of apoptosis .


Therefore , it is likely that PML bodies function in an antiviral capacity .


SUMO-1 modification of PML is known to be required for the formation of PML bodies .

SUMO-1 modification of <protein>PML</protein> is known to be required for the formation of PML bodies .


To examine whether Epstein-Barr virus ( EBV ) lytic replication interferes with PML bodies , we expressed the EBV immediate-early genes BZLF1 ( Z ) and BRLF1 ( R ) in EBV-positive cell lines and examined PML localization .

To examine whether Epstein-Barr virus ( EBV ) lytic replication interferes with PML bodies , we expressed the <dna>EBV immediate-early genes</dna> <dna>BZLF1 ( Z )</dna> and <dna>BRLF1 ( R )</dna> in <cell_line>EBV-positive cell lines</cell_line> and examined <protein>PML</protein> localization .


Both Z and R expression resulted in PML dispersion in EBV-positive cells .

Both Z and R expression resulted in <protein>PML</protein> dispersion in <cell_type>EBV-positive cells</cell_type> .


Z but not R expression is sufficient to disrupt PML bodies in EBV-negative cell lines .

Z but not R expression is sufficient to disrupt PML bodies in <cell_line>EBV-negative cell lines</cell_line> .


We show that dispersion of PML bodies by Z requires a portion of the transcriptional activation domain of Z but not the DNA-binding function .

We show that dispersion of PML bodies by <dna>Z</dna> requires a portion of the <dna>transcriptional activation domain</dna> of <dna>Z</dna> but not the DNA-binding function .


As was previously reported for the HSV-1 ICP0 and CMV IE1 proteins , Z reduces the amount of SUMO-1-modified PML .

As was previously reported for the <protein>HSV-1 ICP0 and CMV IE1 proteins</protein> , <dna>Z</dna> reduces the amount of <protein>SUMO-1-modified PML</protein> .


We also found that Z itself is SUMO-1 modified ( through amino acid 12 ) and that Z competes with PML for limiting amounts of SUMO-1 .

We also found that <dna>Z</dna> itself is SUMO-1 modified ( through amino acid 12 ) and that <dna>Z</dna> competes with <protein>PML</protein> for limiting amounts of <protein>SUMO-1</protein> .


These results suggest that disruption of PML bodies is important for efficient lytic replication of EBV .


Furthermore , Z may potentially alter the function of a variety of cellular proteins by inhibiting SUMO-1 modification

Furthermore , <dna>Z</dna> may potentially alter the function of a variety of cellular proteins by inhibiting SUMO-1 modification


Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone : evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese .

Suppression of <protein>nuclear factor-kappaB</protein> and stimulation of <protein>inhibitor kappaB</protein> by troglitazone : evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese .


To elucidate whether troglitazone exerts an antiinflammatory effect in humans , in vivo , we investigated the suppression of nuclear factor kappaB ( NFkappaB ) in mononuclear cells ( MNC ) by this drug .

To elucidate whether troglitazone exerts an antiinflammatory effect in humans , in vivo , we investigated the suppression of <protein>nuclear factor kappaB</protein> ( <protein>NFkappaB</protein> ) in <cell_type>mononuclear cells ( MNC )</cell_type> by this drug .


We measured intranuclear NFkappaB , total cellular NFkappaB , inhibitor kappaB ( IkappaB ) alpha , reactive oxygen species ( ROS ) generation , and p47 ( phox ) subunit ( a key component protein of nicotinamide adenine dinucleotide phosphate oxidase ) in MNC .

We measured <protein>intranuclear NFkappaB</protein> , total <protein>cellular NFkappaB</protein> , <protein>inhibitor kappaB ( IkappaB ) alpha</protein> , reactive oxygen species ( ROS ) generation , and <protein>p47 ( phox ) subunit</protein> ( a key component protein of <protein>nicotinamide adenine dinucleotide phosphate oxidase</protein> ) in <cell_type>MNC</cell_type> .


Plasma tumor necrosis factor ( TNF ) -alpha , soluble intercellular adhesion molecule-1 ( sICAM-1 ) , monocyte chemoattractant protein-1 ( MCP-1 ) , plasminogen activator inhibitor type 1 ( PAI-1 ) , C-reactive protein ( CRP ) , and interleukin ( IL ) -10 ( antiinflammatory cytokine ) concentrations were also measured as mediators of inflammatory activity that are regulated by the proinflammatory transcription factor NFkappaB .

<protein>Plasma tumor necrosis factor ( TNF ) -alpha</protein> , <protein>soluble intercellular adhesion molecule-1</protein> ( <protein>sICAM-1</protein> ) , <protein>monocyte chemoattractant protein-1 ( MCP-1 )</protein> , <protein>plasminogen activator inhibitor type 1</protein> ( <protein>PAI-1</protein> ) , <protein>C-reactive protein ( CRP )</protein> , and <protein>interleukin ( IL ) -10</protein> ( <protein>antiinflammatory cytokine</protein> ) concentrations were also measured as mediators of inflammatory activity that are regulated by the <protein>proinflammatory transcription factor NFkappaB</protein> .


Seven nondiabetic obese patients were given 400 mg troglitazone daily for 4 weeks .


Blood samples were collected before and at weekly intervals thereafter .


MNC were separated ; and the levels of intranuclear NFkappaB , total cellular NFkappaB , IkappaBalpha , and p47 ( phox ) subunit and ROS generation were determined .

<cell_type>MNC</cell_type> were separated ; and the levels of <protein>intranuclear NFkappaB</protein> , total <protein>cellular NFkappaB</protein> , <protein>IkappaBalpha</protein> , and <protein>p47 ( phox ) subunit</protein> and ROS generation were determined .


Plasma was used to measure insulin glucose , TNFalpha , sICAM , MCP-1 , PAI-1 , CRP , and IL-10 .

Plasma was used to measure insulin glucose , <protein>TNFalpha</protein> , <protein>sICAM</protein> , <protein>MCP-1</protein> , <protein>PAI-1</protein> , <protein>CRP</protein> , and <protein>IL-10</protein> .


Plasma insulin concentrations fell significantly at week 1 , from 31.2 +/- 29.1 to 14.2 +/- 11.4 mU/L ( P < 0.01 ) and remained low throughout 4 weeks .


Plasma glucose concentrations did not alter significantly .


There was a fall in intranuclear NFkappaB , total cellular NFkappaB , and p47 ( phox ) subunit , with an increase in cellular IkappaBalpha at week 2 , which persisted until week 4 .

There was a fall in <protein>intranuclear NFkappaB</protein> , total <protein>cellular NFkappaB</protein> , and <protein>p47 ( phox ) subunit</protein> , with an increase in cellular <protein>IkappaBalpha</protein> at week 2 , which persisted until week 4 .


There was a parallel fall in ROS generation by MNC at week 1 ; this progressed and persisted until week 4 ( P < 0.001 ) .

There was a parallel fall in ROS generation by <cell_type>MNC</cell_type> at week 1 ; this progressed and persisted until week 4 ( P < 0.001 ) .


Plasma TNF-alpha , sICAM-1 , MCP-1 , and PAI-1 concentrations fell significantly at week 4 .

Plasma <protein>TNF-alpha</protein> , <protein>sICAM-1</protein> , <protein>MCP-1</protein> , and <protein>PAI-1</protein> concentrations fell significantly at week 4 .


Plasma IL-10 concentration increased significantly , whereas plasma CRP concentrations decreased .

Plasma <protein>IL-10</protein> concentration increased significantly , whereas <protein>plasma CRP</protein> concentrations decreased .


We conclude that troglitazone has an antiinflammatory action that may contribute to its putative antiatherosclerotic effects .


Tyrosine phosphorylation-dependent activation of NF-kappa B .

Tyrosine phosphorylation-dependent activation of <protein>NF-kappa B</protein> .


Requirement for p56 LCK and ZAP-70 protein tyrosine kinases .

Requirement for <protein>p56 LCK and ZAP-70 protein tyrosine kinases</protein> .


Phosphorylation of the N-terminal domain of I kappa B inhibitory subunits induces activation of the transcription factor NF-kappa B .

Phosphorylation of the <protein>N-terminal domain</protein> of <protein>I kappa B inhibitory subunits</protein> induces activation of the <protein>transcription factor NF-kappa B</protein> .


Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome-mediated degradation of I kappa B-alpha , little is known about the mechanisms that lead to release of active NF-kappa B in T cells as a consequence of tyrosine phosphorylation of I kappa B-alpha [ Imbert , V. , Rupec , R.A. , Livolsi , A. , Pahl , H.L. , Traenckner , B.M. , Mueller-Dieckmann , C. , Farahifar , D. , Rossi , B. , Auberger , P. , Baeuerle , P. & Peyron , J.F. ( 1996 ) Cell 86 , 787 -- 798 ] .

Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome-mediated degradation of <protein>I kappa B-alpha</protein> , little is known about the mechanisms that lead to release of active <protein>NF-kappa B</protein> in <cell_type>T cells</cell_type> as a consequence of tyrosine phosphorylation of <protein>I kappa B-alpha</protein> [ Imbert , V. , Rupec , R.A. , Livolsi , A. , Pahl , H.L. , Traenckner , B.M. , Mueller-Dieckmann , C. , Farahifar , D. , Rossi , B. , Auberger , P. , Baeuerle , P. & Peyron , J.F. ( 1996 ) Cell 86 , 787 -- 798 ] .


The involvement of the tyrosine kinases p56 ( lck ) and ZAP-70 in this reaction is demonstrated here using specific pharmacological inhibitors and Jurkat mutants unable to express these kinases .

The involvement of the <protein>tyrosine kinases</protein> <protein>p56 ( lck )</protein> and <protein>ZAP-70</protein> in this reaction is demonstrated here using specific pharmacological inhibitors and <cell_line>Jurkat mutants</cell_line> unable to express these <protein>kinases</protein> .


Although the inhibitors prevented both pervanadate-induced phosphorylation of I kappa B-alpha on Tyr42 and NF-kappa B activation , we observed that , in p56 ( lck ) -deficient Jurkat mutants , NF-kappa B could still associate with I kappa B-alpha despite phosphorylation on Tyr42 .

Although the inhibitors prevented both pervanadate-induced phosphorylation of <protein>I kappa B-alpha</protein> on Tyr42 and <protein>NF-kappa B</protein> activation , we observed that , in <cell_line>p56 ( lck ) -deficient Jurkat mutants</cell_line> , <protein>NF-kappa B</protein> could still associate with <protein>I kappa B-alpha</protein> despite phosphorylation on Tyr42 .


Furthermore , the SH2 domain of p56 ( lck ) appeared to be required for pervanadate-induced NF-kappa B activation but not for Tyr42 phosphorylation .

Furthermore , the <protein>SH2 domain</protein> of <protein>p56 ( lck )</protein> appeared to be required for pervanadate-induced <protein>NF-kappa B</protein> activation but not for Tyr42 phosphorylation .


These results show that p56 ( lck ) and ZAP-70 are key components of the signaling pathway that leads to phosphotyrosine-dependent NF-kappa B activation in T cells and confirm that tyrosine kinases must control at least two different steps to induce activation of NF-kappa B .

These results show that <protein>p56 ( lck )</protein> and <protein>ZAP-70</protein> are key components of the signaling pathway that leads to phosphotyrosine-dependent <protein>NF-kappa B</protein> activation in <cell_type>T cells</cell_type> and confirm that <protein>tyrosine kinases</protein> must control at least two different steps to induce activation of <protein>NF-kappa B</protein> .


Finally , we show that H ( 2 ) O ( 2 ) , which stimulates p56 ( lck ) and ZAP-70 in T cells , is an activator of NF-kappa B through tyrosine phosphorylation of I kappa B-alpha .

Finally , we show that H ( 2 ) O ( 2 ) , which stimulates <protein>p56 ( lck )</protein> and <protein>ZAP-70</protein> in <cell_type>T cells</cell_type> , is an activator of <protein>NF-kappa B</protein> through tyrosine phosphorylation of <protein>I kappa B-alpha</protein> .


Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia .

Specific missense mutations in <dna>NEMO</dna> result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia .


The gene that encodes nuclear factor kappaB ( NF-kappaB ) essential modulator ( or NEMO , also known as IKKgamma ) is required for activation of the transcription factor NF-kappaB .

The gene that encodes <dna>nuclear factor kappaB ( NF-kappaB ) essential modulator</dna> ( or <dna>NEMO</dna> , also known as <dna>IKKgamma</dna> ) is required for activation of the <protein>transcription factor NF-kappaB</protein> .


We describe mutations in the putative zinc-finger domain of NEMO that result in an X-linked primary immunodeficiency characterized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia ( XHM-ED ) .

We describe mutations in the <protein>putative zinc-finger domain</protein> of <protein>NEMO</protein> that result in an X-linked primary immunodeficiency characterized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia ( XHM-ED ) .


These mutations prevent CD40 ligand ( CD40L ) -mediated degradation of inhibitor of NF-kappaB alpha ( IkappaB-alpha ) and account for the following observations : B cells from XHM-ED patients are unable to undergo immunoglobulin class-switch recombination and antigen-presenting cells ( APCs ) are unable to synthesize the NF-kappaB-regulated cytokines interleukin 12 ( IL-12 ) or tumor necrosis factor alpha ( TNF-alpha ) when stimulated with CD40L .

These mutations prevent <protein>CD40 ligand</protein> ( <protein>CD40L</protein> ) -mediated degradation of inhibitor of <protein>NF-kappaB alpha</protein> ( <protein>IkappaB-alpha</protein> ) and account for the following observations : <cell_type>B cells</cell_type> from XHM-ED patients are unable to undergo immunoglobulin class-switch recombination and <cell_type>antigen-presenting cells</cell_type> ( <cell_type>APCs</cell_type> ) are unable to synthesize the <protein>NF-kappaB-regulated cytokines</protein> <protein>interleukin 12</protein> ( <protein>IL-12</protein> ) or <protein>tumor necrosis factor alpha</protein> ( <protein>TNF-alpha</protein> ) when stimulated with <protein>CD40L</protein> .


Nevertheless , innate immunity is preserved in XHM-ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan 's antigen ( SAC ) .

Nevertheless , innate immunity is preserved in XHM-ED patients because <cell_type>APCs</cell_type> retain the capacity to respond to stimulation by lipopolysaccharide or <protein>Staphylococcus aureus Cowan 's antigen</protein> ( <protein>SAC</protein> ) .


Overall , the phenotype observed in XHM-ED patients shows that the putative zinc-finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40 -mediated NF-kappaB activation for B cell immunoglobulin class-switching .

Overall , the phenotype observed in XHM-ED patients shows that the <protein>putative zinc-finger domain</protein> of <protein>NEMO</protein> has a regulatory function and demonstrates the definite requirement of <protein>CD40</protein> -mediated NF-kappaB activation for <cell_type>B cell</cell_type> immunoglobulin class-switching .


Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all-trans retinoic acid metabolites .

Granulocytic differentiation of <cell_type>human NB4 promyelocytic leukemia cells</cell_type> induced by all-trans retinoic acid metabolites .


The metabolism of all-trans retinoic acid ( ATRA ) has been reported to be partly responsible for the in vivo resistance to ATRA seen in the treatment of human acute promyelocytic leukemia ( APL ) .


However , ATRA metabolism appears to be involved in the growth inhibition of several cancer cell lines in vitro .

However , ATRA metabolism appears to be involved in the growth inhibition of several <cell_line>cancer cell lines</cell_line> in vitro .


The purpose of this study was to evaluate the in vitro activity of the principal metabolites of ATRA [ 4-hydroxy-retinoic acid ( 4-OH-RA ) , 18-hydroxy-retinoic acid ( 18-OH-RA ) , 4-oxo-retinoic acid ( 4-oxo-RA ) , and 5 , 6-epoxy-retinoic acid ( 5 , 6-epoxy-RA ) ] in NB4 , a human promyelocytic leukemia cell line that exhibits the APL diagnostic t ( 15 ; 17 ) chromosomal translocation and expresses the PML-RAR alpha fusion protein .

The purpose of this study was to evaluate the in vitro activity of the principal metabolites of ATRA [ 4-hydroxy-retinoic acid ( 4-OH-RA ) , 18-hydroxy-retinoic acid ( 18-OH-RA ) , 4-oxo-retinoic acid ( 4-oxo-RA ) , and 5 , 6-epoxy-retinoic acid ( 5 , 6-epoxy-RA ) ] in <cell_line>NB4 , a human promyelocytic leukemia cell line</cell_line> that exhibits the APL diagnostic t ( 15 ; 17 ) chromosomal translocation and expresses the <protein>PML-RAR alpha fusion protein</protein> .


We established that the four ATRA metabolites were indeed formed by the NB4 cells in vitro .

We established that the four ATRA metabolites were indeed formed by the <cell_line>NB4 cells</cell_line> in vitro .


NB4 cell growth was inhibited ( 69-78 % at 120 h ) and cell cycle progression in the G1 phase ( 82-85 % at 120 h ) was blocked by ATRA and all of the metabolites at 1 microM concentration .


ATRA and its metabolites could induce NB4 cells differentiation with similar activity , as evaluated by cell morphology , by the nitroblue tetrazolium reduction test ( 82-88 % at 120 h ) or by the expression of the maturation specific cell surface marker CD11c .

ATRA and its metabolites could induce <cell_line>NB4 cells</cell_line> differentiation with similar activity , as evaluated by cell morphology , by the nitroblue tetrazolium reduction test ( 82-88 % at 120 h ) or by the expression of the <protein>maturation specific cell surface marker CD11c</protein> .


In addition , nuclear body reorganization to macropunctated structures , as well as the degradation of PML-RAR alpha , was found to be similar for ATRA and all of its metabolites .

In addition , nuclear body reorganization to macropunctated structures , as well as the degradation of <protein>PML-RAR alpha</protein> , was found to be similar for ATRA and all of its metabolites .


Comparison of the relative potency of the retinoids using the nitroblue tetrazolium reduction test showed effective concentrations required to differentiate 50 % of cells in 72 h as follows : ATRA , 15.8 +/- 1.7 nM ; 4-oxo-RA , 38.3 +/- 1.3 nM ; 18-OH-RA , 55.5 +/- 1.8 nM ; 4-OH-RA , 79.8 +/- 1.8 nM ; and 5 , 6-epoxy-RA , 99.5 +/- 1.5 nM .


The ATRA metabolites were found to exert their differentiation effects via the RAR alpha nuclear receptors , because the RAR alpha-specific antagonist BMS614 blocked metabolite-induced CD11c expression in NB4 cells .

The ATRA metabolites were found to exert their differentiation effects via the <protein>RAR alpha nuclear receptors</protein> , because the RAR alpha-specific antagonist BMS614 blocked metabolite-induced CD11c expression in <cell_line>NB4 cells</cell_line> .


These data demonstrate that the principal ATRA Phase 1 metabolites can elicit leukemia cell growth inhibition and differentiation in vitro through the RAR alpha signaling pathway , and they suggest that these metabolites may play a role in ATRA antileukemic activity in vivo .

These data demonstrate that the principal ATRA Phase 1 metabolites can elicit <cell_type>leukemia cell</cell_type> growth inhibition and differentiation in vitro through the RAR alpha signaling pathway , and they suggest that these metabolites may play a role in ATRA antileukemic activity in vivo .


Expression of oestrogen and progesterone receptors by mast cells alone , but not lymphocytes , macrophages or other immune cells in human upper airways .

Expression of <protein>oestrogen and progesterone receptors</protein> by <cell_type>mast cells</cell_type> alone , but not <cell_type>lymphocytes</cell_type> , <cell_type>macrophages</cell_type> or other <cell_type>immune cells</cell_type> in human upper airways .


BACKGROUND : Nasal polyposis often coexists with asthma in airway inflammatory conditions characterised by the infiltration of a range of immune cells .

BACKGROUND : Nasal polyposis often coexists with asthma in airway inflammatory conditions characterised by the infiltration of a range of <cell_type>immune cells</cell_type> .


A potentially important role for ovarian hormones has been implicated in airway inflammation but the cellular target for such action is not known .


METHODS : Expression of oestrogen receptors ( ER ) and progesterone receptors ( PR ) was examined using immunohistochemistry in formalin fixed nasal polyp tissues from 47 subjects .

METHODS : Expression of <protein>oestrogen receptors</protein> ( <protein>ER</protein> ) and <protein>progesterone receptors</protein> ( <protein>PR</protein> ) was examined using immunohistochemistry in formalin fixed nasal polyp tissues from 47 subjects .


The cells positive for ER or PR were confirmed by spatial location , dual immunolabelling , and histochemical staining .

The cells positive for <protein>ER</protein> or <protein>PR</protein> were confirmed by spatial location , dual immunolabelling , and histochemical staining .


RESULTS : Consistent with the known features of nasal polyps , CD4+ ( T helper/inducer ) , CD8+ ( cytotoxic/suppressor ) , CD68+ ( macrophages ) , mast cells , eosinophils and neutrophils were all clearly detected by their relevant monoclonal antibodies or appropriate histochemical staining , but only mast cells tested positive for ER /PR labelling with their polyclonal and monoclonal antibodies .

RESULTS : Consistent with the known features of nasal polyps , <cell_type>CD4+ ( T helper/inducer )</cell_type> , <cell_type>CD8+ ( cytotoxic/suppressor )</cell_type> , <cell_type>CD68+</cell_type> ( <cell_type>macrophages</cell_type> ) , <cell_type>mast cells</cell_type> , <cell_type>eosinophils</cell_type> and <cell_type>neutrophils</cell_type> were all clearly detected by their relevant <protein>monoclonal antibodies</protein> or appropriate histochemical staining , but only <cell_type>mast cells</cell_type> tested positive for <protein>ER</protein> /PR labelling with their <protein>polyclonal and monoclonal antibodies</protein> .


The frequencies for expression were 61.7 % for ER positive and 59.6 % for PR positive cells .

The frequencies for expression were 61.7 % for <cell_type>ER positive</cell_type> and 59.6 % for <cell_type>PR positive cells</cell_type> .


The expression of ER / PR was independent of patient sex and age but was highly correlated with the numbers of mast cells ( r = 0.973 , p < 0.001 for ER ; r = 0.955 , p < 0.001 for PR ) .

The expression of <protein>ER</protein> / <protein>PR</protein> was independent of patient sex and age but was highly correlated with the numbers of <cell_type>mast cells</cell_type> ( r = 0.973 , p < 0.001 for <protein>ER</protein> ; r = 0.955 , p < 0.001 for <protein>PR</protein> ) .


Fewer than 5 % of mast cells were found to be negative for ER / PR expression .

Fewer than 5 % of <cell_type>mast cells</cell_type> were found to be negative for <protein>ER</protein> / <protein>PR</protein> expression .


CONCLUSIONS : Mast cells alone , but not lymphocytes , macrophages , or other immune cells , express ER / PR in human upper airways .

CONCLUSIONS : <cell_type>Mast cells</cell_type> alone , but not <cell_type>lymphocytes</cell_type> , <cell_type>macrophages</cell_type> , or other <cell_type>immune cells</cell_type> , express <protein>ER</protein> / <protein>PR</protein> in human upper airways .


Numerous ER/PR positive mast cells exist in nasal polyps , indicating that this may be a major route for the involvement of sex hormones in airway inflammation when exposed to the higher and varying concentration of oestrogen and progesterone characteristic of females .

Numerous <cell_type>ER/PR positive mast cells</cell_type> exist in nasal polyps , indicating that this may be a major route for the involvement of sex hormones in airway inflammation when exposed to the higher and varying concentration of oestrogen and progesterone characteristic of females .


NF kappa b signaling in posthypoxic endothelial cells : relevance to E-selectin expression and neutrophil adhesion .

NF kappa b signaling in <cell_type>posthypoxic endothelial cells</cell_type> : relevance to E-selectin expression and neutrophil adhesion .


Our previous studies have implicated the nuclear transcription factor kappa B ( NF kappa B ) in the regulation of adhesion molecule expression in endothelial cells exposed to anoxia-reoxygenation ( A/R ) or a redox imbalance .

Our previous studies have implicated the nuclear transcription factor kappa B ( <protein>NF kappa B</protein> ) in the regulation of <protein>adhesion molecule</protein> expression in <cell_type>endothelial cells</cell_type> exposed to anoxia-reoxygenation ( A/R ) or a redox imbalance .


The objectives of this study were ( 1 ) to define the kinetics of NF kappa B activation by examining I kappa B alpha degradation and the nuclear translocation of p65 in response to A/R or redox imbalance ( induced by treatment of cells with diamide and buthionine sulfoximine ) and ( 2 ) to determine whether the signal for I kappa B alpha degradation , nuclear translocation of p65 , and E-selectin -mediated neutrophil adhesion is related to the activity of protein tyrosine kinase ( PTK ) , protein tyrosine phosphatase ( PTPase ) and/or protein kinase C ( PKC ) .

The objectives of this study were ( 1 ) to define the kinetics of <protein>NF kappa B</protein> activation by examining I kappa B alpha degradation and the nuclear translocation of <protein>p65</protein> in response to A/R or redox imbalance ( induced by treatment of cells with diamide and buthionine sulfoximine ) and ( 2 ) to determine whether the signal for I kappa B alpha degradation , nuclear translocation of <protein>p65</protein> , and <protein>E-selectin</protein> -mediated neutrophil adhesion is related to the activity of <protein>protein tyrosine kinase</protein> ( <protein>PTK</protein> ) , <protein>protein tyrosine phosphatase</protein> ( <protein>PTPase</protein> ) and/or <protein>protein kinase C</protein> ( <protein>PKC</protein> ) .


The results demonstrate that both A/R and redox imbalance led to I kappa B alpha degradation within 30 min and the concomitant appearance of p65 in the nucleus , consistent with rapid cytosolic activation of NF kappa B and subsequent nuclear translocation of the activated p65 subunit .

The results demonstrate that both A/R and redox imbalance led to I kappa B alpha degradation within 30 min and the concomitant appearance of <protein>p65</protein> in the nucleus , consistent with rapid cytosolic activation of <protein>NF kappa B</protein> and subsequent nuclear translocation of the <protein>activated p65 subunit</protein> .


Inhibition of PKC blocked I kappa B alpha degradation and p65 translocation in A/R-challenged , but not redox-altered , endothelial cells .

Inhibition of <protein>PKC</protein> blocked <protein>I kappa B alpha</protein> degradation and <protein>p65</protein> translocation in A/R-challenged , but not redox-altered , <cell_type>endothelial cells</cell_type> .


However , both A/R- and redox-induced NF kappa B activation was blocked by inhibition of PTK .

However , both A/R- and redox-induced NF kappa B activation was blocked by inhibition of <protein>PTK</protein> .


Similarly , A/R-induced E-selectin expression and neutrophil-endothelial cell adhesion were blocked by inhibition of PKC or PTK , while only PTK inhibited the redox-induced adhesion response .

Similarly , A/R-induced E-selectin expression and neutrophil-endothelial cell adhesion were blocked by inhibition of <protein>PKC</protein> or <protein>PTK</protein> , while only <protein>PTK</protein> inhibited the redox-induced adhesion response .


Pretreatment of cells with N-acetyl cysteine effectively blocked A/R- or redox-induced I kappa B degradation and significantly attenuated the respective neutrophil adhesion responses .


Collectively , these findings indicate that A/R-induced E-selectin expression and neutrophil-endothelial cell adhesion are mediated by both PKC and PTK , which signal rapid activation of NF kappa B .

Collectively , these findings indicate that A/R-induced E-selectin expression and neutrophil-endothelial cell adhesion are mediated by both <protein>PKC</protein> and <protein>PTK</protein> , which signal rapid activation of <protein>NF kappa B</protein> .


This A/R-induced NF kappa B signaling response appears to be mediated , at least in part , by intracellular redox imbalance .

This A/R-induced <protein>NF kappa B</protein> signaling response appears to be mediated , at least in part , by intracellular redox imbalance .


Copyright 2001 S. Karger AG , Basel


Induction of apoptosis in human lymphocytes by the herbicide 2 , 4-dichlorophenoxyacetic acid .

Induction of apoptosis in <cell_type>human lymphocytes</cell_type> by the herbicide 2 , 4-dichlorophenoxyacetic acid .


Dimethylammonium salt of 2 , 4-dichlorophenoxyacetic acid ( DMA-2 , 4-D ) is a widely used herbicide that is considered moderately toxic .


In the present study we found that DMA-2 , 4-D is able to cause apoptosis in peripheral blood lymphocytes of healthy individuals and Jurkat T cells .

In the present study we found that DMA-2 , 4-D is able to cause apoptosis in <cell_type>peripheral blood lymphocytes</cell_type> of healthy individuals and <cell_line>Jurkat T cells</cell_line> .


Apoptosis induced by DMA-2 , 4-D was dose and time dependent , independent of Fas , TNF receptor 1 or the aromatic hydrocarbon receptor , and involved disruption of the mitochondrial transmembrane potential and activation of caspase-9 .

Apoptosis induced by DMA-2 , 4-D was dose and time dependent , independent of <protein>Fas</protein> , <protein>TNF receptor 1</protein> or the <protein>aromatic hydrocarbon receptor</protein> , and involved disruption of the mitochondrial transmembrane potential and activation of <protein>caspase-9</protein> .


ZVAD-FMK , a broad-spectrum inhibitor of caspases , blocked DMA-2 , 4-D-induced apoptosis completely .

ZVAD-FMK , a broad-spectrum inhibitor of <protein>caspases</protein> , blocked DMA-2 , 4-D-induced apoptosis completely .


While an inhibitor of caspase-9 , as well as caspase-9 and caspase-3 inhibitors in combination , strongly blocked DMA-2 , 4-D-induced apoptosis , an inhibitor of caspase-3 had a moderate inhibitory effect .

While an inhibitor of <protein>caspase-9</protein> , as well as <protein>caspase-9</protein> and caspase-3 inhibitors in combination , strongly blocked DMA-2 , 4-D-induced apoptosis , an inhibitor of <protein>caspase-3</protein> had a moderate inhibitory effect .


Unlike Fas -mediated apoptosis , the initiator caspase , caspase-8 , was not involved in DMA-2 , 4-D-induced apoptosis .

Unlike <protein>Fas</protein> -mediated apoptosis , the <protein>initiator caspase</protein> , <protein>caspase-8</protein> , was not involved in DMA-2 , 4-D-induced apoptosis .


Transfection of Jurkat cells with Bcl-2 prevented DMA-2 , 4-D-induced disruption of the mitochondrial transmembrane potential and led to a complete blockage of apoptosis .

Transfection of <cell_line>Jurkat cells</cell_line> with <protein>Bcl-2</protein> prevented DMA-2 , 4-D-induced disruption of the mitochondrial transmembrane potential and led to a complete blockage of apoptosis .


Our data indicate that DMA-2 , 4-D kills human lymphocytes by initiating apoptosis via a direct effect on mitochondria .

Our data indicate that DMA-2 , 4-D kills <cell_type>human lymphocytes</cell_type> by initiating apoptosis via a direct effect on mitochondria .


The activation of caspases occurs downstream of mitochondrial damage , and the dysfunction of mitochondria appears to be sufficient for triggering all downstream events leading to apoptosis .

The activation of <protein>caspases</protein> occurs downstream of mitochondrial damage , and the dysfunction of mitochondria appears to be sufficient for triggering all downstream events leading to apoptosis .


Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1 .

Inhibition of Th1 differentiation by <protein>IL-6</protein> is mediated by <protein>SOCS1</protein> .


Interleukin 6 ( IL-6 ) is a cytokine produced by immune and nonimmune cells and exhibits functional pleiotropy and redundancy .

<protein>Interleukin 6</protein> ( <protein>IL-6</protein> ) is a <protein>cytokine</protein> produced by <cell_type>immune and nonimmune cells</cell_type> and exhibits functional pleiotropy and redundancy .


IL-6 plays an important role in the differentiation of several cell types .

<protein>IL-6</protein> plays an important role in the differentiation of several cell types .


Here , we describe a novel function of IL-6 : the negative regulation of CD4 + Th1 cell differentiation .

Here , we describe a novel function of <protein>IL-6</protein> : the negative regulation of <protein>CD4</protein> + Th1 cell differentiation .


While IL-6 -directed CD4 + Th2 differentiation is mediated by IL-4 , inhibition of Th1 differentiation by IL-6 is independent of IL-4 .

While <protein>IL-6</protein> -directed <protein>CD4</protein> + Th2 differentiation is mediated by <protein>IL-4</protein> , inhibition of Th1 differentiation by <protein>IL-6</protein> is independent of <protein>IL-4</protein> .


IL-6 upregulates suppressor of cytokine signaling 1 ( SOCS1 ) expression in activated CD4+ T cells , thereby interfering with signal transducer and activator of transcription 1 ( STAT1 ) phosphorylation induced by interferon gamma ( IFNgamma ) .

<protein>IL-6</protein> upregulates <protein>suppressor of cytokine signaling 1</protein> ( <protein>SOCS1</protein> ) expression in <cell_type>activated CD4+ T cells</cell_type> , thereby interfering with <protein>signal transducer and activator of transcription 1</protein> ( <protein>STAT1</protein> ) phosphorylation induced by <protein>interferon gamma</protein> ( <protein>IFNgamma</protein> ) .


Inhibition of IFNgamma receptor-mediated signals by IL-6 prevents autoregulation of IFNgamma gene expression by IFNgamma during CD4+ T cell activation , thereby preventing Th1 differentiation .

Inhibition of <protein>IFNgamma</protein> receptor-mediated signals by <protein>IL-6</protein> prevents autoregulation of <dna>IFNgamma gene</dna> expression by <protein>IFNgamma</protein> during <cell_type>CD4+ T cell</cell_type> activation , thereby preventing Th1 differentiation .


Thus , IL-6 promotes CD4 + Th2 differentiation and inhibits Th1 differentiation by two independent molecular mechanisms .

Thus , <protein>IL-6</protein> promotes <protein>CD4</protein> + Th2 differentiation and inhibits Th1 differentiation by two independent molecular mechanisms .


Interaction between CCAAT/enhancer binding protein and cyclic AMP response element binding protein 1 regulates human immunodeficiency virus type 1 transcription in cells of the monocyte/macrophage lineage .

Interaction between <protein>CCAAT/enhancer binding protein</protein> and <protein>cyclic AMP response element binding protein 1</protein> regulates human immunodeficiency virus type 1 transcription in cells of the <cell_type>monocyte/macrophage lineage</cell_type> .


Recent observations have shown two CCAAT/enhancer binding protein ( C/EBP ) binding sites to be critically important for efficient human immunodeficiency virus type 1 ( HIV-1 ) replication within cells of the monocyte/macrophage lineage , a cell type likely involved in transport of the virus to the brain .

Recent observations have shown two <dna>CCAAT/enhancer binding protein ( C/EBP ) binding sites</dna> to be critically important for efficient human immunodeficiency virus type 1 ( HIV-1 ) replication within cells of the <cell_type>monocyte/macrophage lineage</cell_type> , a cell type likely involved in transport of the virus to the brain .


Additionally , sequence variation at C/EBP site I , which lies immediately upstream of the distal nuclear factor kappa B site and immediately downstream of a binding site for activating transcription factor ( ATF ) / cyclic AMP response element binding protein ( CREB ) , has been shown to affect HIV-1 long terminal repeat ( LTR ) activity .

Additionally , sequence variation at <dna>C/EBP site I</dna> , which lies immediately upstream of the <dna>distal nuclear factor kappa B site</dna> and immediately downstream of a binding site for <protein>activating transcription factor</protein> ( <protein>ATF</protein> ) / <protein>cyclic AMP response element binding protein</protein> ( <protein>CREB</protein> ) , has been shown to affect <dna>HIV-1 long terminal repeat</dna> ( <dna>LTR</dna> ) activity .


Given that C/EBP proteins have been shown to interact with many other transcription factors including members of the ATF/CREB family , we proceeded to determine whether an adjacent ATF/CREB binding site could affect C/EBP protein binding to C/EBP site I .

Given that <protein>C/EBP proteins</protein> have been shown to interact with many other <protein>transcription factors</protein> including members of the <protein>ATF/CREB family</protein> , we proceeded to determine whether an adjacent <dna>ATF/CREB binding site</dna> could affect <protein>C/EBP protein</protein> binding to <dna>C/EBP site I</dna> .


Electrophoretic mobility shift analyses indicated that selected ATF/CREB site variants assisted in the recruitment of C/EBP proteins to an adjacent , naturally occurring , low-affinity C/EBP site .

Electrophoretic mobility shift analyses indicated that selected <dna>ATF/CREB site variants</dna> assisted in the recruitment of <protein>C/EBP proteins</protein> to an adjacent , naturally occurring , low-affinity <dna>C/EBP site</dna> .


This biophysical interaction appears to occur via at least two mechanisms .


First , low amounts of CREB-1 and C/EBP appear to heterodimerize and bind to a site consisting of a half site from both the ATF/CREB and C/EBP binding sites .

First , low amounts of <protein>CREB-1</protein> and <protein>C/EBP</protein> appear to heterodimerize and bind to a site consisting of a half site from both the <dna>ATF/CREB and C/EBP binding sites</dna> .


In addition , CREB-1 homodimers bind to the ATF/CREB site and recruit C/EBP dimers to their cognate weak binding sites .

In addition , <protein>CREB-1 homodimers</protein> bind to the <dna>ATF/CREB site</dna> and recruit <protein>C/EBP dimers</protein> to their cognate <dna>weak binding sites</dna> .


This interaction is reciprocal , since C/EBP dimer binding to a strong C/EBP site leads to enhanced CREB-1 recruitment to ATF/CREB sites that are weakly bound by CREB .

This interaction is reciprocal , since <protein>C/EBP dimer</protein> binding to a strong <dna>C/EBP site</dna> leads to enhanced <protein>CREB-1</protein> recruitment to <dna>ATF/CREB sites</dna> that are weakly bound by <protein>CREB</protein> .


Sequence variation at both C/EBP and ATF/CREB sites affects the molecular interactions involved in mediating both of these mechanisms .

Sequence variation at both <dna>C/EBP and ATF/CREB sites</dna> affects the molecular interactions involved in mediating both of these mechanisms .


Most importantly , sequence variation at the ATF/CREB binding site affected basal LTR activity as well as LTR function following interleukin-6 stimulation , a treatment that leads to increases in C/EBP activation .

Most importantly , sequence variation at the <dna>ATF/CREB binding site</dna> affected basal <dna>LTR</dna> activity as well as <dna>LTR</dna> function following <protein>interleukin-6</protein> stimulation , a treatment that leads to increases in C/EBP activation .


Thus , HIV-1 LTR ATF/CREB binding site sequence variation may modulate cellular signaling at the viral promoter through the C/EBP pathway

Thus , <dna>HIV-1 LTR</dna> <dna>ATF/CREB binding site</dna> sequence variation may modulate cellular signaling at the <dna>viral promoter</dna> through the C/EBP pathway


Selective inhibition of interleukin-4 gene expression in human T cells by aspirin .

Selective inhibition of interleukin-4 gene expression in <cell_type>human T cells</cell_type> by aspirin .


Previous studies indicated that aspirin ( acetylsalicylic acid [ ASA ] ) can have profound immunomodulatory effects by regulating cytokine gene expression in several types of cells .


This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce interleukin ( IL ) -4 secretion and RNA expression in freshly isolated and mitogen-primed human CD4+ T cells .

This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce <protein>interleukin ( IL ) -4</protein> secretion and RNA expression in <cell_type>freshly isolated and mitogen-primed human CD4+ T cells</cell_type> .


In contrast , ASA did not affect IL-13 , interferon-gamma , and IL-2 expression .

In contrast , ASA did not affect <protein>IL-13</protein> , <protein>interferon-gamma</protein> , and <protein>IL-2</protein> expression .


ASA inhibited IL-4 , but not IL-2 , promoter-driven chloramphenicol acetyltransferase expression in transiently transfected Jurkat T cells .

ASA inhibited <protein>IL-4</protein> , but not <protein>IL-2</protein> , promoter-driven chloramphenicol acetyltransferase expression in transiently transfected <cell_line>Jurkat T cells</cell_line> .


The structurally unrelated nonsteroidal anti-inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in T cells , whereas the weak cyclo-oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting IL-4 expression and promoter activity .

The structurally unrelated nonsteroidal anti-inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in <cell_type>T cells</cell_type> , whereas the weak cyclo-oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting <protein>IL-4</protein> expression and promoter activity .


The inhibitory effect of ASA on IL-4 transcription was not mediated by decreased nuclear expression of the known salicylate target nuclear factor ( NF ) -kappaB and was accompanied by reduced binding of an inducible factor to an IL-4 promoter region upstream of , but not overlapping , the NF of activated T cells- and NF-kappaB-binding P1 element .

The inhibitory effect of ASA on IL-4 transcription was not mediated by decreased nuclear expression of the known <protein>salicylate target nuclear factor ( NF ) -kappaB</protein> and was accompanied by reduced binding of an inducible factor to an <dna>IL-4 promoter region</dna> upstream of , but not overlapping , the <dna>NF of activated T cells- and NF-kappaB-binding P1 element</dna> .


It is concluded that anti-inflammatory salicylates , by means of a previously unrecognized mechanism of action , can influence the nature of adaptive immune responses by selectively inhibiting the expression of IL-4 , a critical effector of these responses , in CD4+ T cells .

It is concluded that anti-inflammatory salicylates , by means of a previously unrecognized mechanism of action , can influence the nature of adaptive immune responses by selectively inhibiting the expression of <protein>IL-4</protein> , a critical effector of these responses , in <cell_type>CD4+ T cells</cell_type> .


Molecular and cellular mediators of interleukin-1 -dependent acute inflammatory arthritis .

Molecular and cellular mediators of <protein>interleukin-1</protein> -dependent acute inflammatory arthritis .


OBJECTIVE : To examine the molecular and cellular mechanisms in a model of acute inflammatory monarticular arthritis induced by methylated bovine serum albumin ( mBSA ) and interleukin-1 ( IL-1 ) .

OBJECTIVE : To examine the molecular and cellular mechanisms in a model of acute inflammatory monarticular arthritis induced by <protein>methylated bovine serum albumin</protein> ( <protein>mBSA</protein> ) and <protein>interleukin-1</protein> ( <protein>IL-1</protein> ) .


METHODS : Mice were injected intraarticularly with mBSA on day 0 and subcutaneously with recombinant human IL-1beta on days 0-2 .

METHODS : Mice were injected intraarticularly with <protein>mBSA</protein> on day 0 and subcutaneously with <protein>recombinant human IL-1beta</protein> on days 0-2 .


At day 7 , knee joints were removed and assessed histologically .


Flow cytometry and RNase protection were used to analyze IL-1 -dependent events .

Flow cytometry and RNase protection were used to analyze <protein>IL-1</protein> -dependent events .


RESULTS : C57BL/6 ( B6 ) , 129/Sv , and ( B6 x 129/ Sv ) F1 hybrid mice , all H-2b strains , were susceptible to mBSA /IL-1-induced arthritis , whereas C3H/HeJ ( H-2k ) mice were not .

RESULTS : C57BL/6 ( B6 ) , 129/Sv , and ( B6 x 129/ Sv ) F1 hybrid mice , all H-2b strains , were susceptible to <protein>mBSA</protein> /IL-1-induced arthritis , whereas C3H/HeJ ( H-2k ) mice were not .


B6 mice lacking T and B cells ( RAG1-/- ) or major histocompatibility complex ( MHC ) class II antigens ( MHCII-/- ) , and B6 mice treated with a CD4+ T cell-depleting monoclonal antibody , were resistant to disease .

B6 mice lacking <cell_type>T and B cells</cell_type> ( RAG1-/- ) or <protein>major histocompatibility complex ( MHC ) class II antigens</protein> ( MHCII-/- ) , and B6 mice treated with a <protein>CD4+ T cell-depleting monoclonal antibody</protein> , were resistant to disease .


In contrast , B cell-deficient ( muMT/ muMT ) mice developed arthritis at an incidence and severity similar to that of controls .


RelB-deficient ( RelB-/- ) bone marrow chimeric mice had arthritis that was significantly reduced in incidence and severity .


In B6 mice , flow cytometry demonstrated an IL-1-dependent leukocyte infiltration into the synovial compartment and RNase protection assays revealed induction of messenger RNA ( mRNA ) for the chemokines monocyte chemoattractant protein 1 , macrophage inhibitory protein 2 ( MIP-2 ) , RANTES , MIP-1alpha , and MIP-1beta , in vivo and in vitro .

In B6 mice , flow cytometry demonstrated an <cell_type>IL-1-dependent leukocyte</cell_type> infiltration into the synovial compartment and RNase protection assays revealed induction of <rna>messenger RNA</rna> ( <rna>mRNA</rna> ) for the <protein>chemokines</protein> <protein>monocyte chemoattractant protein 1</protein> , <protein>macrophage inhibitory protein 2</protein> ( <protein>MIP-2</protein> ) , <protein>RANTES</protein> , <protein>MIP-1alpha</protein> , and <protein>MIP-1beta</protein> , in vivo and in vitro .


CONCLUSION : Arthritis induced by mBSA / IL-1 is strain specific and dependent on CD4+ T lymphocytes and at least partially on RelB , but not on B lymphocytes or antibody .

CONCLUSION : Arthritis induced by <protein>mBSA</protein> / <protein>IL-1</protein> is strain specific and dependent on <cell_type>CD4+ T lymphocytes</cell_type> and at least partially on <protein>RelB</protein> , but not on <cell_type>B lymphocytes</cell_type> or <protein>antibody</protein> .


IL-1 contributes to leukocyte recruitment to the synovium and directly induces chemokine mRNA production by synovial cells .

<protein>IL-1</protein> contributes to leukocyte recruitment to the synovium and directly induces chemokine mRNA production by <cell_type>synovial cells</cell_type> .


This model of acute monarticular arthritis is particularly suitable for further investigations into cell-mediated immunity in arthritis and the role of IL-1 .

This model of acute monarticular arthritis is particularly suitable for further investigations into cell-mediated immunity in arthritis and the role of <protein>IL-1</protein> .


Positive and negative regulation of granulopoiesis by endogenous RARalpha .

Positive and negative regulation of granulopoiesis by <protein>endogenous RARalpha</protein> .


Acute promyelocytic leukemia ( APL ) is always associated with chromosomal translocations that disrupt the retinoic acid receptor alpha ( RARalpha ) gene .

Acute promyelocytic leukemia ( APL ) is always associated with chromosomal translocations that disrupt the <dna>retinoic acid receptor alpha ( RARalpha ) gene</dna> .


Whether these translocations relate to a role for endogenous RARalpha in normal granulopoiesis remains uncertain because most studies addressing this question have used non-physiological overexpression systems .

Whether these translocations relate to a role for <protein>endogenous RARalpha</protein> in normal granulopoiesis remains uncertain because most studies addressing this question have used non-physiological overexpression systems .


Granulocyte differentiation in cells derived from RARalpha-deficient ( RARalpha ( -/- ) ) mice was studied and evaluated in the context of agonist-bound and ligand-free RARalpha .

Granulocyte differentiation in cells derived from RARalpha-deficient ( RARalpha ( -/- ) ) mice was studied and evaluated in the context of <protein>agonist-bound and ligand-free RARalpha</protein> .


Our results demonstrate that RARalpha is dispensable for granulopoiesis , as RARalpha ( -/- ) mice have a normal granulocyte population despite an impaired ability to respond to retinoids .

Our results demonstrate that <protein>RARalpha</protein> is dispensable for granulopoiesis , as RARalpha ( -/- ) mice have a <cell_type>normal granulocyte population</cell_type> despite an impaired ability to respond to retinoids .


However , although it is not absolutely required , RARalpha can bidirectionally modulate granulopoiesis .

However , although it is not absolutely required , <protein>RARalpha</protein> can bidirectionally modulate granulopoiesis .


RARalpha stimulates differentiation in response to exogenous retinoic acid .

<protein>RARalpha</protein> stimulates differentiation in response to exogenous retinoic acid .


Furthermore , endogenous retinoids control granulopoiesis in vivo , as either vitamin A-deficient mice or animals treated with an RAR antagonist accumulate more immature granulocytes in their bone marrow .

Furthermore , endogenous retinoids control granulopoiesis in vivo , as either vitamin A-deficient mice or animals treated with an RAR antagonist accumulate more <cell_type>immature granulocytes</cell_type> in their bone marrow .


Conversely , RARalpha acts to limit differentiation in the absence of ligand because granulocyte precursors from RARalpha ( -/- ) mice differentiate earlier in culture .

Conversely , <protein>RARalpha</protein> acts to limit differentiation in the absence of <protein>ligand</protein> because <cell_type>granulocyte precursors</cell_type> from RARalpha ( -/- ) mice differentiate earlier in culture .


Thus , the block in granulopoiesis exerted by RARalpha fusion proteins expressed in APL cells may correspond to an amplification of a normal function of unliganded RARalpha .

Thus , the block in granulopoiesis exerted by <protein>RARalpha</protein> <protein>fusion proteins</protein> expressed in <cell_type>APL cells</cell_type> may correspond to an amplification of a normal function of <protein>unliganded RARalpha</protein> .


Expression and function of a stem cell promoter for the murine CBFalpha2 gene : distinct roles and regulation in natural killer and T cell development .

Expression and function of a <dna>stem cell promoter</dna> for the <dna>murine CBFalpha2 gene</dna> : distinct roles and regulation in <cell_type>natural killer and T cell</cell_type> development .


The Runt family transcription factor CBFalpha2 ( AML1 , PEBP2alphaB , or Runx1 ) is required by hematopoietic stem cells and expressed at high levels in T-lineage cells .

The <protein>Runt family transcription factor</protein> <protein>CBFalpha2</protein> ( <protein>AML1</protein> , <protein>PEBP2alphaB</protein> , or <protein>Runx1</protein> ) is required by <cell_type>hematopoietic stem cells</cell_type> and expressed at high levels in <cell_type>T-lineage cells</cell_type> .


In human T cells CBFalpha2 is usually transcribed from a different promoter ( distal promoter ) than in myeloid cells ( proximal promoter ) , but the developmental and functional significance of this promoter switch has not been known .

In <cell_type>human T cells</cell_type> <protein>CBFalpha2</protein> is usually transcribed from a <dna>different promoter</dna> ( <dna>distal promoter</dna> ) than in <cell_type>myeloid cells</cell_type> ( <dna>proximal promoter</dna> ) , but the developmental and functional significance of this promoter switch has not been known .


Here , we report that both coding and noncoding sequences of the distal 5 ' end are highly conserved between the human and the murine genes , and the distal promoter is responsible for the overwhelming majority of CBFalpha2 expression in murine hematopoietic stem cells as well as in T cells .

Here , we report that both <dna>coding and noncoding sequences</dna> of the <dna>distal 5 ' end</dna> are highly conserved between the <dna>human and the murine genes</dna> , and the <dna>distal promoter</dna> is responsible for the overwhelming majority of CBFalpha2 expression in murine <cell_type>hematopoietic stem cells</cell_type> as well as in <cell_type>T cells</cell_type> .


Distal promoter activity is maintained throughout T cell development and at lower levels in B cell development , but downregulated in natural killer cell development .


The distal N-terminal isoform binds to functionally important regulatory sites from known target genes with two- to threefold higher affinity than the proximal N-terminal isoform .

The <dna>distal N-terminal isoform</dna> binds to functionally important <dna>regulatory sites</dna> from known <dna>target genes</dna> with two- to threefold higher affinity than the <dna>proximal N-terminal isoform</dna> .


Neither full-length isoform alters growth of a myeloid cell line under nondifferentiating conditions , but the proximal isoform selectively delays mitotic arrest of the cell line under differentiating conditions , resulting in the generation of greater numbers of neutrophils .

Neither <dna>full-length isoform</dna> alters growth of a <cell_line>myeloid cell line</cell_line> under nondifferentiating conditions , but the <dna>proximal isoform</dna> selectively delays mitotic arrest of the cell line under differentiating conditions , resulting in the generation of greater numbers of <cell_type>neutrophils</cell_type> .


Constitutive PI3-K activity is essential for proliferation , but not survival , of Theileria parva-transformed B cells .

Constitutive PI3-K activity is essential for proliferation , but not survival , of <cell_type>Theileria parva-transformed B cells</cell_type> .


Theileria is an intracellular parasite that causes lymphoproliferative disorders in cattle , and infection of leucocytes induces a transformed phenotype similar to tumour cells , but the mechanisms by which the parasite induces this phenotype are not understood .

Theileria is an intracellular parasite that causes lymphoproliferative disorders in cattle , and infection of <cell_type>leucocytes</cell_type> induces a transformed phenotype similar to <cell_type>tumour cells</cell_type> , but the mechanisms by which the parasite induces this phenotype are not understood .


Here , we show that infected B lymphocytes display constitutive phosphoinositide 3-kinase ( PI3-K ) activity , which appears to be necessary for proliferation , but not survival .

Here , we show that <cell_type>infected B lymphocytes</cell_type> display constitutive phosphoinositide 3-kinase ( PI3-K ) activity , which appears to be necessary for proliferation , but not survival .


Importantly , we demonstrate that one mechanism by which PI3-K mediates the proliferation of infected B lymphocytes is through the induction of a granulocyte-monocyte colony-stimulating factor ( GM-CSF ) -dependent autocrine loop .

Importantly , we demonstrate that one mechanism by which <protein>PI3-K</protein> mediates the proliferation of <cell_type>infected B lymphocytes</cell_type> is through the induction of a <protein>granulocyte-monocyte colony-stimulating factor</protein> ( <protein>GM-CSF</protein> ) -dependent autocrine loop .


PI3-K induction of GM-CSF appears to be at the transcriptional level and , consistently , we demonstrate that PI3-K is also involved in the constitutive induction of AP-1 and NF-kappaB , which characterizes Theileria-infected leucocytes .

<protein>PI3-K</protein> induction of <protein>GM-CSF</protein> appears to be at the transcriptional level and , consistently , we demonstrate that <protein>PI3-K</protein> is also involved in the constitutive induction of <protein>AP-1</protein> and <protein>NF-kappaB</protein> , which characterizes Theileria-infected <cell_type>leucocytes</cell_type> .


Taken together , our results highlight a novel strategy exploited by the intracellular parasite Theileria to induce continued proliferation of its host leucocyte .

Taken together , our results highlight a novel strategy exploited by the intracellular parasite Theileria to induce continued proliferation of its <cell_type>host leucocyte</cell_type> .


Lymphokine dependence of STAT3 activation produced by surface immunoglobulin cross-linking and by phorbol ester plus calcium ionophore treatment in B cells .

<protein>Lymphokine</protein> dependence of STAT3 activation produced by surface immunoglobulin cross-linking and by phorbol ester plus calcium ionophore treatment in <cell_type>B cells</cell_type> .


Stimulation of B cells by surface immunoglobulin ( sIg ) triggering , or through the mitogenic combination of phorbol ester and calcium ionophore , is accompanied by activation of STAT transcription factors .

Stimulation of <cell_type>B cells</cell_type> by <protein>surface immunoglobulin</protein> ( <protein>sIg</protein> ) triggering , or through the mitogenic combination of phorbol ester and calcium ionophore , is accompanied by activation of <protein>STAT transcription factors</protein> .


The mechanism responsible for the delayed nuclear accumulation of phosphorylated STAT3 was examined in detail , focusing on the role of B cell-derived lymphokines .

The mechanism responsible for the delayed nuclear accumulation of <protein>phosphorylated STAT3</protein> was examined in detail , focusing on the role of <protein>B cell-derived lymphokines</protein> .


sIg -induced activation of STAT3 was partially inhibited in B cells obtained from IL-6- or IL-10-deficient mice , and was partially blocked by neutralizing antibodies directed against either of these lymphokines .

<protein>sIg</protein> -induced activation of <protein>STAT3</protein> was partially inhibited in <cell_type>B cells</cell_type> obtained from IL-6- or IL-10-deficient mice , and was partially blocked by <protein>neutralizing antibodies</protein> directed against either of these <protein>lymphokines</protein> .


sIg -induced STAT3 activation was completely inhibited by combining IL-6- and IL-10-specific neutralizing antibodies , or by adding individual neutralizing antibodies to B cells obtained from lymphokine-deficient animals .

<protein>sIg</protein> -induced STAT3 activation was completely inhibited by combining <protein>IL-6- and IL-10-specific neutralizing antibodies</protein> , or by adding individual <protein>neutralizing antibodies</protein> to <cell_type>B cells</cell_type> obtained from lymphokine-deficient animals .


In contrast , IL-10 alone appeared to account for STAT3 activation resulting from B cell stimulation with phorbol ester and calcium ionophore .

In contrast , <protein>IL-10</protein> alone appeared to account for STAT3 activation resulting from B cell stimulation with phorbol ester and calcium ionophore .


In keeping with these results , soluble IL-6 and IL-10 were found in supernatant fluid obtained from stimulated B cells .

In keeping with these results , soluble <protein>IL-6</protein> and <protein>IL-10</protein> were found in supernatant fluid obtained from <cell_type>stimulated B cells</cell_type> .


This work indicates that a lymphokine pathway is responsible for STAT3 activation that occurs late after B cell stimulation , and points out differences in B cell activation that result from stimulation through the antigen receptor and through pharmacological mimicry of signaling mediators .

This work indicates that a lymphokine pathway is responsible for STAT3 activation that occurs late after B cell stimulation , and points out differences in B cell activation that result from stimulation through the <protein>antigen receptor</protein> and through pharmacological mimicry of <protein>signaling mediators</protein> .


Transcription factor AP-4 is a ligand for immunoglobulin-kappa promoter E-box elements .

<protein>Transcription factor AP-4</protein> is a <protein>ligand</protein> for <dna>immunoglobulin-kappa promoter E-box elements</dna> .


Immunoglobulin ( Ig ) -kappa promoters from humans and mice share conserved sequences .

<dna>Immunoglobulin ( Ig ) -kappa promoters</dna> from humans and mice share <dna>conserved sequences</dna> .


The octamer element is common to all Ig promoters and pivotal for their function .

The <dna>octamer element</dna> is common to all <dna>Ig promoters</dna> and pivotal for their function .


However , other conserved sequence motifs , that differ between Ig variable gene families , are required for normal promoter function .

However , other <dna>conserved sequence motifs</dna> , that differ between <dna>Ig variable gene families</dna> , are required for normal promoter function .


These conserved motifs do not stimulate transcription in the absence of an octamer .

These conserved motifs do not stimulate transcription in the absence of an <dna>octamer</dna> .


One example is an E-box of the E47/E12 type ( 5'-CAGCTG-3 ' ) , which is found in all promoters of the human and murine Ig-kappa gene subgroups/families , with the exception of subgroups II and VI and their related murine families .

One example is an <dna>E-box</dna> of the <dna>E47/E12 type ( 5'-CAGCTG-3 ' )</dna> , which is found in all promoters of the <dna>human and murine Ig-kappa gene subgroups/families</dna> , with the exception of subgroups II and VI and their related <dna>murine families</dna> .


In the present study we show that the ubiquitously expressed transcription factor AP-4 , and not E47 , interacts specifically with the kappa promoter E-boxes when tested in electrophoretic mobility-shift assays using nuclear extracts derived from human and murine B-cell lines .

In the present study we show that the ubiquitously expressed <protein>transcription factor AP-4</protein> , and not <protein>E47</protein> , interacts specifically with the <dna>kappa promoter E-boxes</dna> when tested in electrophoretic mobility-shift assays using nuclear extracts derived from <cell_line>human and murine B-cell lines</cell_line> .


Furthermore , AP-4 , unlike E47 , did not act as a transactivator , which is in agreement with previous studies on intact kappa promoters , showing that transcription is absent when the octamer element has been mutated .

Furthermore , <protein>AP-4</protein> , unlike <protein>E47</protein> , did not act as a <protein>transactivator</protein> , which is in agreement with previous studies on intact <dna>kappa promoters</dna> , showing that transcription is absent when the <dna>octamer element</dna> has been mutated .


Based on these data , and the conservation of the 5'-CAGCTG-3 ' motif among human and murine kappa promoters , we propose that AP-4 is the major ligand for Ig-kappa promoter E-boxes .

Based on these data , and the conservation of the <dna>5'-CAGCTG-3 ' motif</dna> among <dna>human and murine kappa promoters</dna> , we propose that <protein>AP-4</protein> is the <protein>major ligand</protein> for <dna>Ig-kappa promoter E-boxes</dna> .


A 16-mer peptide ( RQIKIWFQNRRMKWKK ) from antennapedia preferentially targets the Class I pathway .


Translocation of antigenic peptides into the cytosol of antigen presenting cells facilitates proteosomal processing and loading into Class I molecules for MHC presentation on the cell surface .

Translocation of antigenic peptides into the cytosol of <cell_type>antigen presenting cells</cell_type> facilitates proteosomal processing and loading into <protein>Class I molecules</protein> for MHC presentation on the cell surface .


The DNA binding domain of the Drosophila transcription factor ( Antennapedia ) , a 60 amino acid protein , is rapidly taken up by cells and has been fused to selected antigens to enhance their immunogenicity .

The <protein>DNA binding domain</protein> of the <protein>Drosophila transcription factor</protein> ( <protein>Antennapedia</protein> ) , a <protein>60 amino acid protein</protein> , is rapidly taken up by cells and has been fused to selected <protein>antigens</protein> to enhance their immunogenicity .


We now demonstrate that a 16 amino acid peptide from antennapedia can facilitate the cytoplasmic uptake of CTL epitope 9-mer peptides .


Synthetic peptides were made containing the 16-mer antennapedia peptide linked in tandem to the ovalbumin SIINFEKL CTL peptide .


The peptide complex was shown to rapidly internalise into APCs by confocal microscopy .

The peptide complex was shown to rapidly internalise into <cell_type>APCs</cell_type> by confocal microscopy .


This peptide induced CTL in C57BL/6 mice and protected them against growth of an ovalbumin expressing tumour cell line ( E.G7-OVA ) .

This peptide induced <cell_type>CTL</cell_type> in C57BL/6 mice and protected them against growth of an <cell_line>ovalbumin expressing tumour cell line</cell_line> ( <cell_line>E.G7-OVA</cell_line> ) .


The ability of the hybrid peptide to be processed and presented by APCs was similar , whether the SIINFEKL sequence was appended at the C-terminus or N-terminus of the Antennapedia peptide .

The ability of the hybrid peptide to be processed and presented by <cell_type>APCs</cell_type> was similar , whether the SIINFEKL sequence was appended at the <protein>C-terminus</protein> or <protein>N-terminus</protein> of the Antennapedia peptide .


The production of synthetic peptides containing other CTL peptide epitopes may be useful for priming CTLs in vitro and in vivo

The production of synthetic peptides containing other CTL peptide epitopes may be useful for priming <cell_type>CTLs</cell_type> in vitro and in vivo


Bone marrow cells promote TH2 polarization and inhibit virus-specific CTL generation .

<cell_type>Bone marrow cells</cell_type> promote TH2 polarization and inhibit virus-specific CTL generation .


This laboratory recently reported that human bone marrow cells ( BMC ) inhibit the generation of virus-specific CTL in culture .

This laboratory recently reported that <cell_type>human bone marrow cells</cell_type> ( <cell_type>BMC</cell_type> ) inhibit the generation of <cell_type>virus-specific CTL</cell_type> in culture .


The culture supernatants contained increased levels of prostaglandin E ( 2 ) ( PGE ( 2 ) ) ( shown to favor TH2 cell development ) and also inhibited EBV-CTL effector cell development .

The culture supernatants contained increased levels of <protein>prostaglandin E ( 2 ) ( PGE ( 2 ) )</protein> ( shown to favor TH2 cell development ) and also inhibited EBV-CTL effector cell development .


In this study , we obtained PBL from Epstein-Barr virus ( EBV ) IgG antibody positive kidney transplant recipients ( R ) and their living-related donors ( LRD ) one year after renal transplantation .

In this study , we obtained <cell_type>PBL</cell_type> from Epstein-Barr virus ( EBV ) <protein>IgG antibody</protein> positive kidney transplant recipients ( R ) and their living-related donors ( LRD ) one year after renal transplantation .


EBV-specific CTL were then generated in vitro by stimulating PBL with autologous EBV-transformed B cells ( EBV-B ) in the presence or absence of autologous BMC .

<cell_type>EBV-specific CTL</cell_type> were then generated in vitro by stimulating <cell_type>PBL</cell_type> with autologous <cell_type>EBV-transformed B cells</cell_type> ( <cell_type>EBV-B</cell_type> ) in the presence or absence of <cell_type>autologous BMC</cell_type> .


The addition of BMC to the EBV-CTL generation cultures increased the intracellular expression in CD3+ cells of IL-4 , -5 , -6 , -10 , and -13 .

The addition of <cell_type>BMC</cell_type> to the <cell_type>EBV-CTL generation cultures</cell_type> increased the intracellular expression in <cell_type>CD3+ cells</cell_type> of <protein>IL-4 , -5 , -6 , -10 , and -13</protein> .


These CD3+ cells also expressed increased levels of the TH2 associated receptor CCR3 .

These <cell_type>CD3+ cells</cell_type> also expressed increased levels of the <protein>TH2 associated receptor CCR3</protein> .


Inhibition was even observed by preparing EBV-CTL generating cultures in trans-wells that separated the autologous BMC from the PBL + EBV-B .

Inhibition was even observed by preparing <cell_type>EBV-CTL generating cultures</cell_type> in trans-wells that separated the <cell_type>autologous BMC</cell_type> from the <cell_type>PBL</cell_type> + <cell_type>EBV-B</cell_type> .


It was then observed that CD3+ cells obtained after 7 days of culture in the presence of autologous BMC could be used as inhibitors of EBV-CTL generation .

It was then observed that <cell_type>CD3+ cells</cell_type> obtained after 7 days of culture in the presence of <cell_type>autologous BMC</cell_type> could be used as inhibitors of EBV-CTL generation .


Protein Kinase A ( PKA ) , a cAMP kinase that is involved in the upregulation of TH2 cytokine activity , was increased in EBV-CTL cultures by the presence of BMC .

<protein>Protein Kinase A</protein> ( <protein>PKA</protein> ) , a <protein>cAMP kinase</protein> that is involved in the upregulation of <protein>TH2 cytokine</protein> activity , was increased in <cell_type>EBV-CTL cultures</cell_type> by the presence of <cell_type>BMC</cell_type> .


Additionally , IL-4-mediated signal transduction and activation of transcription ( STAT-6 ) phosphorylation was slightly increased .

Additionally , IL-4-mediated signal transduction and activation of transcription ( <protein>STAT-6</protein> ) phosphorylation was slightly increased .


These results show that the BMC inhibition is mediated by soluble factors ( cytokines ) and that cell-cell contact in this autologous system is not required , so that BMC ( at least partially , via cytokine production ) promote TH2 polarization in culture .

These results show that the <cell_type>BMC</cell_type> inhibition is mediated by <protein>soluble factors</protein> ( <protein>cytokines</protein> ) and that cell-cell contact in this autologous system is not required , so that <cell_type>BMC</cell_type> ( at least partially , via cytokine production ) promote TH2 polarization in culture .


Moreover , TH2 cells induced by culturing with autologous BMC directly inhibit EBV-CTL generation , and TH2 associated PKA , CCR3 , and STAT-6 phosphorylation are enhanced by BMC .

Moreover , <cell_type>TH2 cells</cell_type> induced by culturing with <cell_type>autologous BMC</cell_type> directly inhibit EBV-CTL generation , and <protein>TH2</protein> associated <protein>PKA</protein> , <protein>CCR3</protein> , and <protein>STAT-6</protein> phosphorylation are enhanced by <cell_type>BMC</cell_type> .


Reduction in DNA binding activity of the transcription factor Pax-5a in B lymphocytes of aged mice .

Reduction in DNA binding activity of the <protein>transcription factor</protein> <protein>Pax-5a</protein> in <cell_type>B lymphocytes</cell_type> of aged mice .