Inhibition of pro-inflammatory transcription factors such as activator protein ( AP ) -1 , signal transducers and activators of transcription ( STATs ) , nuclear factor of activated T cells ( NFAT ) and nuclear factor ( NF ) -kappa B is thought to be a major action of glucocorticoids .

Inhibition of <protein>pro-inflammatory transcription factors</protein> such as <protein>activator protein ( AP ) -1</protein> , <protein>signal transducers and activators of transcription</protein> ( <protein>STATs</protein> ) , <protein>nuclear factor of activated T cells</protein> ( <protein>NFAT</protein> ) and <protein>nuclear factor ( NF ) -kappa B</protein> is thought to be a major action of glucocorticoids .


Acetylation of histones allows unwinding of the local DNA structure and enables RNA polymerase II to enhance gene transcription .

Acetylation of <protein>histones</protein> allows unwinding of the <dna>local DNA structure</dna> and enables <protein>RNA polymerase II</protein> to enhance gene transcription .


Histone acetylation is regulated by a balance between the activity of histone acetyltransferases ( HATs ) and histone deacetylases ( HDACs ) .

Histone acetylation is regulated by a balance between the activity of <protein>histone acetyltransferases</protein> ( <protein>HATs</protein> ) and <protein>histone deacetylases</protein> ( <protein>HDACs</protein> ) .


GR acts as a direct inhibitor of NF-kappa B-induced HAT activity and also by recruiting HDAC2 to the NF-kappa B/HAT complex .

<protein>GR</protein> acts as a direct inhibitor of NF-kappa B-induced HAT activity and also by recruiting <protein>HDAC2</protein> to the <protein>NF-kappa B/HAT complex</protein> .


A sub-group of patients with glucocorticoid-insensitive asthma have an inability to induce histone acetylation in response to dexamethasone suggesting reduced expression of a GR-specific HAT .

A sub-group of patients with glucocorticoid-insensitive asthma have an inability to induce histone acetylation in response to dexamethasone suggesting reduced expression of a <protein>GR-specific HAT</protein> .


This suggests that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases .


Identification of the precise mechanism by which activated GR recruits HDAC2 may reveal new targets for the development of drugs that may dissociate the antiinflammatory actions of glucocorticoids from their side effects that are largely due to gene induction .

Identification of the precise mechanism by which <protein>activated GR</protein> recruits <protein>HDAC2</protein> may reveal new targets for the development of drugs that may dissociate the antiinflammatory actions of glucocorticoids from their side effects that are largely due to gene induction .


Copyright Academic Press .


Differential ultraviolet-B-induced immunomodulation in XPA , XPC , and CSB DNA repair-deficient mice .


Ultraviolet B irradiation has serious consequences for cellular immunity and can suppress the rejection of skin tumors and the resistance to infectious diseases .


DNA damage plays a crucial role in these immunomodulatory effects of ultraviolet B , as impaired repair of ultraviolet-B-induced DNA damage has been shown to cause suppression of cellular immunity .


Ultraviolet-B-induced DNA damage is repaired by the nucleotide excision repair mechanism very efficiently .


Nucleotide excision repair comprises two subpathways : transcription-coupled and global genome repair .


In this study the immunologic consequences of specific nucleotide excision repair defects in three mouse models , XPA , XPC , and CSB mutant mice , were investigated .


XPA mice carry a total nucleotide excision repair defect , whereas XPC and CSB mice only lack global genome and transcription-coupled nucleotide excision repair , respectively .


Our data demonstrate that cellular immune parameters in XPA , XPC , and CSB mice are normal compared with their wild-type ( control ) littermates .


This may indicate that the reported altered cellular responses in xeroderma pigmentosum patients are not constitutive but could be due to external factors , such as ultraviolet B .


Upon exposure to ultraviolet B , only XPA mice are very sensitive to ultraviolet-B-induced inhibition of Th1-mediated contact hypersensitivity responses and interferon-gamma production in skin draining lymph nodes .

Upon exposure to ultraviolet B , only XPA mice are very sensitive to ultraviolet-B-induced inhibition of Th1-mediated contact hypersensitivity responses and <protein>interferon-gamma</protein> production in skin draining lymph nodes .


Lipopolysaccharide-stimulated tumor necrosis factor alpha and interleukin-10 production are significantly augmented in both XPA and CSB mice after ultraviolet B exposure .

Lipopolysaccharide-stimulated <protein>tumor necrosis factor alpha</protein> and <protein>interleukin-10</protein> production are significantly augmented in both XPA and CSB mice after ultraviolet B exposure .


Lymph node cell numbers were increased very significantly in XPA , mildly increased in CSB , and not in XPC mice .


In general XPC mice do not exhibit any indication of enhanced ultraviolet B susceptibility with regard to the immune parameters analyzed .


These data suggest that both global genome repair and transcription-coupled repair are needed to prevent immunomodulation by ultraviolet B , whereas transcription-coupled repair is the major DNA repair subpathway of nucleotide excision repair that prevents the acute ultraviolet-B-induced effects such as erythema .


Biomechanical strain induces class a scavenger receptor expression in human monocyte/macrophages and THP-1 cells : a potential mechanism of increased atherosclerosis in hypertension .

Biomechanical strain induces class a <protein>scavenger receptor</protein> expression in <cell_type>human monocyte/macrophages</cell_type> and <cell_type>THP-1 cells</cell_type> : a potential mechanism of increased atherosclerosis in hypertension .


BACKGROUND : Although hypertension is an important risk factor for the development of atherosclerosis , the mechanisms for this interaction are incompletely described .


Previous studies have suggested that biomechanical strain regulates macrophage phenotype .


We tested the hypothesis that biomechanical strain can induce expression of the class A scavenger receptor ( SRA ) , an important lipoprotein receptor in atherogenesis .

We tested the hypothesis that biomechanical strain can induce expression of the <protein>class A scavenger receptor</protein> ( <protein>SRA</protein> ) , an important <protein>lipoprotein receptor</protein> in atherogenesis .


METHODS AND RESULTS : Human monocyte/macrophages or THP-1 cells were cultured in a device that imposes uniform biaxial cyclic 1-Hz strains of 0 % , 1 % , 2 % , or 3 % , and SRA expression was analyzed .

METHODS AND RESULTS : <cell_type>Human monocyte/macrophages</cell_type> or <cell_type>THP-1 cells</cell_type> were cultured in a device that imposes uniform biaxial cyclic 1-Hz strains of 0 % , 1 % , 2 % , or 3 % , and <protein>SRA</protein> expression was analyzed .


Mechanical strains induced SRA mRNA ( 3.5+/-0.6-fold at 3 % strain for 48 hours , P < 0.01 ) and SRA protein in THP-1 cells in an amplitude-dependent manner .

Mechanical strains induced <rna>SRA mRNA</rna> ( 3.5+/-0.6-fold at 3 % strain for 48 hours , P < 0.01 ) and <protein>SRA protein</protein> in <cell_type>THP-1 cells</cell_type> in an amplitude-dependent manner .


This induction was accompanied by augmented expression of the class B scavenger receptor CD36 ( 2.8+/-0.3-fold , P < 0.001 ) but not by increased peroxisome proliferator-activated receptor-gamma expression .

This induction was accompanied by augmented expression of the <protein>class B scavenger receptor CD36</protein> ( 2.8+/-0.3-fold , P < 0.001 ) but not by increased <protein>peroxisome proliferator-activated receptor-gamma</protein> expression .


To evaluate this effect in vivo , apolipoprotein E ( -/- ) mice were randomly assigned to receive standard chow , a high-cholesterol diet , or a high-cholesterol diet with hypertension induced by angiotensin II infusion for 8 weeks .


Immunohistochemistry revealed that among macrophages in atherosclerotic lesions of the aorta , the proportion of macrophages with SRA expression was highest in hypertensive animals on a high-cholesterol diet ( 43.9+/-0.7 % , versus 12.0+/-2.0 % for normotensive animals on a high-cholesterol diet and 4.7+/-4.7 % for animals on standard chow ; P < 0.001 ) .

Immunohistochemistry revealed that among <cell_type>macrophages</cell_type> in atherosclerotic lesions of the aorta , the proportion of <cell_type>macrophages</cell_type> with <protein>SRA</protein> expression was highest in hypertensive animals on a high-cholesterol diet ( 43.9+/-0.7 % , versus 12.0+/-2.0 % for normotensive animals on a high-cholesterol diet and 4.7+/-4.7 % for animals on standard chow ; P < 0.001 ) .


CONCLUSIONS : Biomechanical strain induces SRA expression by monocyte/macrophages , suggesting a novel mechanism for promotion of atherosclerosis in hypertensive patients .

CONCLUSIONS : Biomechanical strain induces <protein>SRA</protein> expression by <cell_type>monocyte/macrophages</cell_type> , suggesting a novel mechanism for promotion of atherosclerosis in hypertensive patients .


High glucose induces MCP-1 expression partly via tyrosine kinase-AP-1 pathway in peritoneal mesothelial cells .

High glucose induces MCP-1 expression partly via tyrosine kinase-AP-1 pathway in <cell_type>peritoneal mesothelial cells</cell_type> .


BACKGROUND : High glucose in peritoneal dialysis solutions has been implicated in the pathogenesis of peritoneal fibrosis in chronic ambulatory peritoneal dialysis ( CAPD ) patients .


However , the mechanisms are not very clear .


Peritoneal macrophages seem to participate in the process of peritoneal fibrosis and monocyte chemoattractant protein-1 ( MCP-1 ) plays a key role in the recruitment of monocytes toward the peritoneal cavity .

<cell_type>Peritoneal macrophages</cell_type> seem to participate in the process of peritoneal fibrosis and <protein>monocyte chemoattractant protein-1</protein> ( <protein>MCP-1</protein> ) plays a key role in the recruitment of <cell_type>monocytes</cell_type> toward the peritoneal cavity .


However , little is known about the effect of high glucose on MCP-1 expression and its signal transduction pathway in human peritoneal mesothelial cells .

However , little is known about the effect of high glucose on <protein>MCP-1</protein> expression and its signal transduction pathway in <cell_type>human peritoneal mesothelial cells</cell_type> .


METHODS : Mesothelial cells were cultured with glucose ( 5 to 100 mmol/L ) or mannitol chronically for up to seven days .

METHODS : <cell_type>Mesothelial cells</cell_type> were cultured with glucose ( 5 to 100 mmol/L ) or mannitol chronically for up to seven days .


MCP-1 expression of mRNA and protein was measured by Northern blot analysis and enzyme-linked immunosorbent assay ( ELISA ) .

<protein>MCP-1</protein> expression of mRNA and protein was measured by Northern blot analysis and enzyme-linked immunosorbent assay ( ELISA ) .


Chemotactic activity of high-glucose-conditioned culture supernatant was measured by chemotactic assay .


To examine the roles of the transcription factors activator protein-1 ( AP-1 ) and nuclear factor-kappaB ( NF-kappaB ) , electrophoretic mobility shift assay ( EMSA ) was performed .

To examine the roles of the <protein>transcription factors</protein> <protein>activator protein-1</protein> ( <protein>AP-1</protein> ) and <protein>nuclear factor-kappaB</protein> ( <protein>NF-kappaB</protein> ) , electrophoretic mobility shift assay ( EMSA ) was performed .


RESULTS : Glucose induced MCP-1 mRNA expression in a time- and dose-dependent manner .

RESULTS : Glucose induced <rna>MCP-1 mRNA</rna> expression in a time- and dose-dependent manner .


MCP-1 protein in cell culture supernant was also increased .

<protein>MCP-1 protein</protein> in cell culture supernant was also increased .


Equivalent concentrations of mannitol had no significant effect .


High-glucose-conditioned supernatant possessed an increased chemotactic activity for monocytes , which was neutralized by anti-MCP-1 antibody .

High-glucose-conditioned supernatant possessed an increased chemotactic activity for <cell_type>monocytes</cell_type> , which was neutralized by <protein>anti-MCP-1 antibody</protein> .


EMSA revealed that glucose increased the AP-1 binding activity in a time- and dose-dependent manner , but not NF-kappaB .

EMSA revealed that glucose increased the <protein>AP-1</protein> binding activity in a time- and dose-dependent manner , but not <protein>NF-kappaB</protein> .


Curcumin , an inhibitor of AP-1 , dose-dependently suppressed the induction of MCP-1 mRNA by high glucose .

Curcumin , an inhibitor of <protein>AP-1</protein> , dose-dependently suppressed the induction of <rna>MCP-1 mRNA</rna> by high glucose .


Tyrosine kinase inhibitors such as genistein ( 12.5 to 50 micromol/L ) and herbimycin A ( 0.1 to 1 micromol/L ) inhibited the high-glucose-induced MCP-1 mRNA expression in a dose-dependent manner , and also suppressed the high-glucose-induced AP-1 binding activity .

Tyrosine kinase inhibitors such as genistein ( 12.5 to 50 micromol/L ) and herbimycin A ( 0.1 to 1 micromol/L ) inhibited the high-glucose-induced <rna>MCP-1 mRNA</rna> expression in a dose-dependent manner , and also suppressed the high-glucose-induced <protein>AP-1</protein> binding activity .


CONCLUSIONS : : High glucose induced mesothelial MCP-1 expression partly via the tyrosine kinase- AP-1 pathway .

CONCLUSIONS : : High glucose induced mesothelial <protein>MCP-1</protein> expression partly via the tyrosine kinase- <protein>AP-1</protein> pathway .


Signal thresholds and modular synergy during expression of costimulatory molecules in B lymphocytes .

Signal thresholds and modular synergy during expression of costimulatory molecules in <cell_type>B lymphocytes</cell_type> .


We analyzed intracellular pathways modulating surface densities of CD80 and CD86 in B cells activated through ligation of the Ag receptor , and the adhesion molecule CD54 .

We analyzed intracellular pathways modulating surface densities of <protein>CD80</protein> and <protein>CD86</protein> in <cell_type>B cells</cell_type> activated through ligation of the <protein>Ag receptor</protein> , and the <protein>adhesion molecule</protein> <protein>CD54</protein> .


Whereas B cell Ag receptor ( BCR ) cross-linking alone stimulated increased expression of CD86 , up-regulation of CD80 required dual stimulation with anti-IgM and anti-CD54 .

Whereas <protein>B cell Ag receptor</protein> ( <protein>BCR</protein> ) cross-linking alone stimulated increased expression of <protein>CD86</protein> , up-regulation of <protein>CD80</protein> required dual stimulation with <protein>anti-IgM</protein> and <protein>anti-CD54</protein> .


The principal downstream component contributed by BCR signaling , toward both CD80 and CD86 induction , was the elevated concentration of free cytoplasmic Ca ( 2+ ) , recruited by way of capacitative influx .

The principal downstream component contributed by <protein>BCR</protein> signaling , toward both <protein>CD80</protein> and <protein>CD86</protein> induction , was the elevated concentration of free cytoplasmic Ca ( 2+ ) , recruited by way of capacitative influx .


This alone was sufficient to generate an increase in CD86 levels .

This alone was sufficient to generate an increase in <protein>CD86</protein> levels .


However , CD80 enhancement required the concerted action of both intracellular Ca ( 2+ ) concentration and CD54-initiated pathways .

However , <protein>CD80</protein> enhancement required the concerted action of both intracellular Ca ( 2+ ) concentration and CD54-initiated pathways .


The nexus between anti-IgM and anti-CD54 stimulation , in the context of CD80 regulation , was identified to involve a self-propagating process of sequential synergy .

The nexus between anti-IgM and anti-CD54 stimulation , in the context of <protein>CD80</protein> regulation , was identified to involve a self-propagating process of sequential synergy .


The first step involved amplified accumulation of intracellular cAMP , as a result of cross-talk between BCR -mobilized Ca ( 2+ ) and CD54-derived signals .

The first step involved amplified accumulation of intracellular cAMP , as a result of cross-talk between <protein>BCR</protein> -mobilized Ca ( 2+ ) and CD54-derived signals .


This then facilitated a second synergistic interaction between Ca ( 2+ ) and cAMP , culminating in CD80 expression .

This then facilitated a second synergistic interaction between Ca ( 2+ ) and cAMP , culminating in <protein>CD80</protein> expression .


Our findings of distinct signal transducer requirements , with the added consequences of cross-talk , offers an explanation for variable modulation of costimulatory molecule expression in response to diverse physiological stimuli .


Importantly , these results also reveal how concentration threshold barriers for recruitment of individual second messengers can be overcome by constructive convergence of signaling modules .


The role of Epstein-Barr virus in neoplastic transformation .


In this review , we focus on new data from basic , translational and clinical research relating to the Epstein-Barr virus ( EBV ) .


Beside its well-known tropism for B lymphocytes and epithelial cells , EBV also infects T lymphocytes , monocytes and granulocytes .

Beside its well-known tropism for <cell_type>B lymphocytes</cell_type> and <cell_type>epithelial cells</cell_type> , EBV also infects <cell_type>T lymphocytes</cell_type> , <cell_type>monocytes</cell_type> and <cell_type>granulocytes</cell_type> .


After primary infection , EBV persists throughout the life span in resting memory B cells , from where it is reactivated upon breakdown of cellular immunity .

After primary infection , EBV persists throughout the life span in <cell_type>resting memory B cells</cell_type> , from where it is reactivated upon breakdown of cellular immunity .


In the process of neoplastic transformation , the EBV-encoded latent membrane protein 1 ( LMP1 ) oncogene represents the major driving force .

In the process of neoplastic transformation , the <dna>EBV-encoded latent membrane protein 1 ( LMP1 ) oncogene</dna> represents the major driving force .


LMP1 acts like a constitutively activated receptor of the tumor necrosis factor receptor family and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the tumor necrosis factor receptor-associated factor ( TRAF ) family .

<protein>LMP1</protein> acts like a <protein>constitutively activated receptor</protein> of the <protein>tumor necrosis factor receptor family</protein> and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the <protein>tumor necrosis factor receptor-associated factor ( TRAF ) family</protein> .


TRAF2 -mediated NF-kappaB activation , AP-1 induction and JAK3 / STAT activation may result in sustained proliferation leading to lymphoma .

<protein>TRAF2</protein> -mediated <protein>NF-kappaB</protein> activation , <protein>AP-1</protein> induction and <protein>JAK3</protein> / <protein>STAT</protein> activation may result in sustained proliferation leading to <cell_line>lymphoma</cell_line> .


The ability of LMP1 to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV-associated latency type II lymphoproliferations like Hodgkin 's disease and angioimmunoblastic lymphadenopathy .

The ability of <protein>LMP1</protein> to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV-associated latency type II lymphoproliferations like Hodgkin 's disease and angioimmunoblastic lymphadenopathy .


The carboxy terminus of LMP1 is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders ( PTLDs ) .

The <protein>carboxy terminus</protein> of <protein>LMP1</protein> is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders ( PTLDs ) .


Cytotoxic T lymphocytes directed against well-characterized epitopes of EBV latency genes represent an already successful and promising therapeutic approach to EBV-associated lymphomas , in particular PTLDs

<cell_type>Cytotoxic T lymphocytes</cell_type> directed against well-characterized epitopes of <dna>EBV latency genes</dna> represent an already successful and promising therapeutic approach to <cell_line>EBV-associated lymphomas</cell_line> , in particular PTLDs


Interferon-alpha drives T cell-mediated immunopathology in the intestine .

<protein>Interferon-alpha</protein> drives T cell-mediated immunopathology in the intestine .


The ability of interferon ( IFN ) -alpha to induce autoimmunity and exacerbate Th1 diseases is well known .

The ability of <protein>interferon ( IFN ) -alpha</protein> to induce autoimmunity and exacerbate Th1 diseases is well known .


We have recently described enhanced expression of IFN-alpha in the mucosa of patients with celiac disease ( CD ) , a gluten-sensitive Th1-mediated enteropathy , characterized by villous atrophy and crypt cell hyperplasia .

We have recently described enhanced expression of <protein>IFN-alpha</protein> in the mucosa of patients with celiac disease ( CD ) , a gluten-sensitive Th1-mediated enteropathy , characterized by villous atrophy and crypt cell hyperplasia .


Previous studies from this laboratory have shown that T cell activation in explant cultures of human fetal gut can also result in villous atrophy and crypt cell hyperplasia .

Previous studies from this laboratory have shown that <cell_type>T cell</cell_type> activation in explant cultures of human fetal gut can also result in villous atrophy and crypt cell hyperplasia .


We have , therefore , examined changes that take place in explant cultures of human fetal gut after activation of T cells with anti-CD3 and/or IFN-alpha .

We have , therefore , examined changes that take place in explant cultures of human fetal gut after activation of <cell_type>T cells</cell_type> with <protein>anti-CD3</protein> and/or <protein>IFN-alpha</protein> .


We show that activation of T cells with anti-CD3 alone elicits a small IFN-gamma and TNF-alpha response with no tissue injury .

We show that activation of <cell_type>T cells</cell_type> with <protein>anti-CD3</protein> alone elicits a small <protein>IFN-gamma</protein> and <protein>TNF-alpha</protein> response with no tissue injury .


Similarly , no changes are seen in explants cultured with IFN-alpha alone .

Similarly , no changes are seen in explants cultured with <protein>IFN-alpha</protein> alone .


However , addition of IFN-alpha with anti-CD3 results in enhanced Th1 response and crypt cell hyperplasia .

However , addition of <protein>IFN-alpha</protein> with <protein>anti-CD3</protein> results in enhanced Th1 response and crypt cell hyperplasia .


This is associated with enhanced phosphorylation of STAT1 , STAT3 , and Fyn , a Src homology tyrosine kinase , which interacts with both TCR and IFN-alpha signal components .

This is associated with enhanced phosphorylation of <protein>STAT1</protein> , <protein>STAT3</protein> , and <protein>Fyn , a Src homology tyrosine kinase</protein> , which interacts with both TCR and IFN-alpha signal components .


Together these data indicate that IFN-alpha can facilitate activation of Th1-reactive cells in the gut and drive immunopathology .

Together these data indicate that <protein>IFN-alpha</protein> can facilitate activation of <cell_type>Th1-reactive cells</cell_type> in the gut and drive immunopathology .


Suppression of tumor necrosis factor alpha production by cAMP in human monocytes : dissociation with mRNA level and independent of interleukin-10 .

Suppression of <protein>tumor necrosis factor alpha</protein> production by cAMP in <cell_type>human monocytes</cell_type> : dissociation with mRNA level and independent of <protein>interleukin-10</protein> .


BACKGROUND : Elevation of cellular cAMP inhibits lipopolysaccharide ( LPS ) -stimulated tumor necrosis factor alpha ( TNF-alpha ) production and increases the expression of interleukin ( IL ) -10 in mononuclear cells .

BACKGROUND : Elevation of cellular cAMP inhibits lipopolysaccharide ( LPS ) -stimulated <protein>tumor necrosis factor alpha</protein> ( <protein>TNF-alpha</protein> ) production and increases the expression of <protein>interleukin ( IL ) -10</protein> in <cell_type>mononuclear cells</cell_type> .


TNF-alpha gene expression obligates activation of the transcription factor nuclear factor kappaB ( NF-kappaB ) .

<dna>TNF-alpha gene</dna> expression obligates activation of the <protein>transcription factor</protein> <protein>nuclear factor kappaB</protein> ( <protein>NF-kappaB</protein> ) .


Exogenous IL-10 inhibits NF-kappaB in monocytes and thus attenuates TNF-alpha production .

Exogenous <protein>IL-10</protein> inhibits <protein>NF-kappaB</protein> in <cell_type>monocytes</cell_type> and thus attenuates <protein>TNF-alpha</protein> production .


We examined the role of endogenous IL-10 in the regulation of NF-kappaB activation and TNF-alpha production in human monocytes by cAMP .

We examined the role of endogenous <protein>IL-10</protein> in the regulation of <protein>NF-kappaB</protein> activation and <protein>TNF-alpha</protein> production in <cell_type>human monocytes</cell_type> by cAMP .


METHODS : Human monocytes were stimulated with Escherichia coli LPS ( 100 ng/ml ) with and without forskolin ( FSK , 50 microM ) or dibutyryl cyclic AMP ( dbcAMP , 100 microM ) .

METHODS : <cell_type>Human monocytes</cell_type> were stimulated with Escherichia coli LPS ( 100 ng/ml ) with and without forskolin ( FSK , 50 microM ) or dibutyryl cyclic AMP ( dbcAMP , 100 microM ) .


Cytokine ( TNF-alpha and IL-10 ) release was measured by immunoassay .

<protein>Cytokine</protein> ( <protein>TNF-alpha</protein> and <protein>IL-10</protein> ) release was measured by immunoassay .


TNF-alpha mRNA was measured by reverse transcription polymerase chain reaction , and NF-kappaB DNA binding activity was assessed by gel mobility shift assay .

<rna>TNF-alpha mRNA</rna> was measured by reverse transcription polymerase chain reaction , and <protein>NF-kappaB</protein> DNA binding activity was assessed by gel mobility shift assay .


RESULTS : cAMP-elevating agents inhibited LPS-stimulated TNF-alpha release ( 0.77 +/- 0.13 ng/10 ( 6 ) cells in LPS + dbcAMP and 0.68 +/- 0.19 ng/10 ( 6 ) cells in LPS + FSK , both P < 0.05 vs 1.61 +/- 0.34 ng/10 ( 6 ) cells in LPS alone ) .

RESULTS : cAMP-elevating agents inhibited LPS-stimulated <protein>TNF-alpha</protein> release ( 0.77 +/- 0.13 ng/10 ( 6 ) cells in LPS + dbcAMP and 0.68 +/- 0.19 ng/10 ( 6 ) cells in LPS + FSK , both P < 0.05 vs 1.61 +/- 0.34 ng/10 ( 6 ) cells in LPS alone ) .


Conversely , cAMP enhanced LPS-stimulated IL-10 release ( 100 +/- 21.5 pg/10 ( 6 ) cells in LPS + dbcAMP and 110 +/- 25.2 pg/10 ( 6 ) cells in LPS + FSK , both P < 0.05 vs 53.3 +/- 12.8 pg/10 ( 6 ) cells in LPS alone ) .

Conversely , cAMP enhanced LPS-stimulated <protein>IL-10</protein> release ( 100 +/- 21.5 pg/10 ( 6 ) cells in LPS + dbcAMP and 110 +/- 25.2 pg/10 ( 6 ) cells in LPS + FSK , both P < 0.05 vs 53.3 +/- 12.8 pg/10 ( 6 ) cells in LPS alone ) .


Neither TNF-alpha mRNA expression nor NF-kappaB activation stimulated by LPS was inhibited by the cAMP-elevating agents .

Neither <rna>TNF-alpha mRNA</rna> expression nor <protein>NF-kappaB</protein> activation stimulated by LPS was inhibited by the cAMP-elevating agents .


Neutralization of IL-10 with a specific antibody did not attenuate the effect of cAMP-elevating agents on TNF-alpha production .

Neutralization of <protein>IL-10</protein> with a specific <protein>antibody</protein> did not attenuate the effect of cAMP-elevating agents on <protein>TNF-alpha</protein> production .


CONCLUSION : The results indicate that cAMP inhibits LPS-stimulated TNF-alpha production through a posttranscriptional mechanism that is independent of endogenous IL-10 .

CONCLUSION : The results indicate that cAMP inhibits LPS-stimulated <protein>TNF-alpha</protein> production through a posttranscriptional mechanism that is independent of endogenous <protein>IL-10</protein> .


Copyright 2001 Academic Press .


Activation of the p21 ( CIP1/WAF1 ) promoter by bone morphogenetic protein-2 in mouse B lineage cells .

Activation of the <dna>p21 ( CIP1/WAF1 ) promoter</dna> by <protein>bone morphogenetic protein-2</protein> in mouse <cell_line>B lineage cells</cell_line> .


BMPs exert a negative growth effect on various types of cells .

<protein>BMPs</protein> exert a negative growth effect on various types of cells .


We have previously reported that BMP-2 inhibited the growth of HS-72 mouse hybridoma cells by inducing p21 ( CIP1/WAF1 ) expression .

We have previously reported that <protein>BMP-2</protein> inhibited the growth of <cell_line>HS-72 mouse hybridoma cells</cell_line> by inducing p21 ( CIP1/WAF1 ) expression .


In the present study , we demonstrated that BMP-2 activated the mouse p21 ( CIP1/WAF1 ) promoter in HS-72 cells , and that a 29-base pair ( b ) region of the promoter ( -1928/-1900 relative to the TATA box ) , conserved between mice and humans , was responsive to BMP-2 as well as expression of Smad1 , Smad4 , and constitutively active mutants of BMP type I receptors .

In the present study , we demonstrated that <protein>BMP-2</protein> activated the mouse <dna>p21 ( CIP1/WAF1 ) promoter</dna> in <cell_line>HS-72 cells</cell_line> , and that a <dna>29-base pair ( b ) region</dna> of the promoter ( -1928/-1900 relative to the <dna>TATA box</dna> ) , conserved between mice and humans , was responsive to <protein>BMP-2</protein> as well as expression of <protein>Smad1</protein> , <protein>Smad4</protein> , and constitutively active mutants of <protein>BMP type I receptors</protein> .


Furthermore , an oligonucleotide containing the 29-b region was found to be associated with Smad4 and phosphorylated Smad1 in the nuclear extract of BMP-2 -stimulated HS-72 cells .

Furthermore , an oligonucleotide containing the <dna>29-b region</dna> was found to be associated with <protein>Smad4</protein> and <protein>phosphorylated Smad1</protein> in the nuclear extract of <protein>BMP-2</protein> -stimulated <cell_line>HS-72 cells</cell_line> .


These results suggested that BMP-2 might activate p21 ( CIP1/WAF1 ) transcription by inducing a binding of Smad4 and Smad1 to the 29-b region in HS-72 cells .

These results suggested that <protein>BMP-2</protein> might activate p21 ( CIP1/WAF1 ) transcription by inducing a binding of <protein>Smad4</protein> and <protein>Smad1</protein> to the <dna>29-b region</dna> in <cell_line>HS-72 cells</cell_line> .


Dendritic cell development from common myeloid progenitors .

<cell_type>Dendritic cell</cell_type> development from common <cell_type>myeloid progenitors</cell_type> .


Dendritic cells ( DCs ) are professional antigen-presenting cells which both initiate adaptive immune responses and control tolerance to self-antigens .

<cell_type>Dendritic cells</cell_type> ( <cell_type>DCs</cell_type> ) are professional <cell_type>antigen-presenting cells</cell_type> which both initiate adaptive immune responses and control tolerance to <protein>self-antigens</protein> .


It has been suggested that these different effects on responder cells depend on subsets of DCs arising from either myeloid or lymphoid hematopoietic origins .

It has been suggested that these different effects on responder cells depend on subsets of <cell_type>DCs</cell_type> arising from either myeloid or lymphoid hematopoietic origins .


In this model , CD8 alpha+ Mac-1- DCs are supposed to be of lymphoid while CD8 alpha- Mac-1+ DCs are supposed to be of myeloid origin .

In this model , <cell_type>CD8 alpha+ Mac-1- DCs</cell_type> are supposed to be of lymphoid while <cell_type>CD8 alpha- Mac-1+ DCs</cell_type> are supposed to be of myeloid origin .


Here we summarize our findings that both CD8 alpha+ and CD8 alpha- DCs can arise from clonogenic common myeloid progenitors ( CMPs ) in both thymus and spleen .

Here we summarize our findings that both <cell_type>CD8 alpha+ and CD8 alpha- DCs</cell_type> can arise from <cell_type>clonogenic common myeloid progenitors</cell_type> ( <cell_type>CMPs</cell_type> ) in both thymus and spleen .


Therefore CD8 alpha expression DCs does not indicate a lymphoid origin and differences among CD8 alpha+ and CD8 alpha- DCs might rather reflect maturation status than ontogeny .

Therefore <protein>CD8 alpha</protein> expression <cell_type>DCs</cell_type> does not indicate a lymphoid origin and differences among <cell_type>CD8 alpha+ and CD8 alpha- DCs</cell_type> might rather reflect maturation status than ontogeny .


On the basis of transplantation studies , it seems likely that most of the DCs in secondary lymphoid organs and a substantial fraction of thymic DCs are myeloid-derived .

On the basis of transplantation studies , it seems likely that most of the <cell_type>DCs</cell_type> in secondary lymphoid organs and a substantial fraction of <cell_type>thymic DCs</cell_type> are myeloid-derived .


Macrophage stimulation with Murabutide , an HIV-suppressive muramyl peptide derivative , selectively activates extracellular signal-regulated kinases 1 and 2 , C/EBPbeta and STAT1 : role of CD14 and Toll-like receptors 2 and 4 .

Macrophage stimulation with Murabutide , an HIV-suppressive muramyl peptide derivative , selectively activates <protein>extracellular signal-regulated kinases 1 and 2</protein> , <protein>C/EBPbeta</protein> and <protein>STAT1</protein> : role of <protein>CD14</protein> and <protein>Toll-like receptors 2 and 4</protein> .


The smallest unit of bacterial peptidoglycans known to be endowed with biological activities is muramyl dipeptide ( MDP ) .


A clinically acceptable synthetic derivative of MDP , namely murabutide ( MB ) , has been found to present interesting pharmacological properties and to suppress HIV-1 replication in monocyte-derived macrophages ( MDM ) .

A clinically acceptable synthetic derivative of MDP , namely murabutide ( MB ) , has been found to present interesting pharmacological properties and to suppress HIV-1 replication in <cell_type>monocyte-derived macrophages</cell_type> ( <cell_type>MDM</cell_type> ) .


We have addressed the signaling events activated in MDM following stimulation with either MB or the potent immunostimulant LPS .

We have addressed the signaling events activated in <cell_type>MDM</cell_type> following stimulation with either MB or the potent immunostimulant LPS .


We also examined whether signaling by muramyl peptides involves the use of cell surface receptors , including CD14 and Toll-like receptor 2 ( TLR2 ) or TLR4 that are known to be signal-transducing receptors for other bacterial cell wall components .

We also examined whether signaling by muramyl peptides involves the use of <protein>cell surface receptors</protein> , including <protein>CD14</protein> and <protein>Toll-like receptor 2</protein> ( <protein>TLR2</protein> ) or <protein>TLR4</protein> that are known to be <protein>signal-transducing receptors</protein> for other bacterial cell wall components .


We demonstrate that , unlike LPS , the safe immunomodulator MB selectively activates extracellular signal-regulated kinases ( Erk ) 1/2 , in the absence of detectable Jun N-terminal kinase ( JNK ) or p38 mitogen-activated kinase activation .

We demonstrate that , unlike LPS , the safe immunomodulator MB selectively activates <protein>extracellular signal-regulated kinases ( Erk ) 1/2</protein> , in the absence of detectable <protein>Jun N-terminal kinase</protein> ( <protein>JNK</protein> ) or <protein>p38 mitogen-activated kinase</protein> activation .


Furthermore , STAT1 activation but weak or no activation of STAT3 or STAT5 respectively , could be detected in MB-stimulated MDM .

Furthermore , <protein>STAT1</protein> activation but weak or no activation of <protein>STAT3</protein> or <protein>STAT5</protein> respectively , could be detected in <cell_type>MB-stimulated MDM</cell_type> .


Using MonoMac6 cells , we observed high C/EBPbeta and AP-1 but weaker and transient NF-kappaB activation by MB .

Using <cell_line>MonoMac6 cells</cell_line> , we observed high <protein>C/EBPbeta</protein> and <protein>AP-1</protein> but weaker and transient <protein>NF-kappaB</protein> activation by MB .


Moreover , the truncated form of C/EBPbeta , known to repress HIV-1 transcription , was detected in extracts from MB-treated THP-1 cells .

Moreover , the truncated form of <protein>C/EBPbeta</protein> , known to repress HIV-1 transcription , was detected in extracts from <cell_line>MB-treated THP-1 cells</cell_line> .


Surprisingly , neither MB nor MDP were able to transduce signals via CD14 and TLR2 or 4 .

Surprisingly , neither MB nor MDP were able to transduce signals via <protein>CD14</protein> and <protein>TLR2 or 4</protein> .


These findings present major differences in the early cell activation process between LPS and muramyl peptides , and strongly argue for the implication of co-receptors other than TLR2 and TLR4 in mediating the signaling events induced by defined subunits of bacterial peptidoglycans .

These findings present major differences in the early cell activation process between LPS and muramyl peptides , and strongly argue for the implication of <protein>co-receptors</protein> other than <protein>TLR2</protein> and <protein>TLR4</protein> in mediating the signaling events induced by defined subunits of bacterial peptidoglycans .


Nuclear peroxisome proliferator-activated receptors alpha and gamma have opposing effects on monocyte chemotaxis in endometriosis .

<protein>Nuclear peroxisome proliferator-activated receptors alpha and gamma</protein> have opposing effects on monocyte chemotaxis in endometriosis .


The peroxisome proliferator-activated receptors ( PPARs ) alpha and gamma are nuclear receptors that play important roles in inflammatory diseases like ulcerative colitis and arthritis .

The <protein>peroxisome proliferator-activated receptors ( PPARs ) alpha and gamma</protein> are <protein>nuclear receptors</protein> that play important roles in inflammatory diseases like ulcerative colitis and arthritis .


In this study , we examined the possible role of PPARs in macrophage attraction into the peritoneal cavity of patients with endometriosis .

In this study , we examined the possible role of <protein>PPARs</protein> in macrophage attraction into the peritoneal cavity of patients with endometriosis .


We identified PPAR-alpha and -gamma messenger RNA by RT-PCR and protein by immunoblotting of lysates of peritoneal macrophages and monocytic U937 cells .

We identified <rna>PPAR-alpha and -gamma</rna> messenger RNA by RT-PCR and protein by immunoblotting of lysates of <cell_type>peritoneal macrophages</cell_type> and <cell_line>monocytic U937 cells</cell_line> .


Using immunocytochemistry , we localized PPAR-alpha and -gamma within the nuclei of both cell types .

Using immunocytochemistry , we localized <protein>PPAR-alpha and -gamma</protein> within the nuclei of both cell types .


Monocyte chemotactic activity of peritoneal fluid from patients with endometriosis was quantified in Boyden chambers .


Migration of U937 cells was increased by WY 14643 and reduced by rosiglitazone .

Migration of <cell_line>U937 cells</cell_line> was increased by WY 14643 and reduced by rosiglitazone .


Peritoneal fluid from patients with endometriosis activated U937 cells transiently transfected with a PPAR-alpha/GAL4 luciferase reporter .

Peritoneal fluid from patients with endometriosis activated <cell_line>U937 cells</cell_line> transiently transfected with a <dna>PPAR-alpha/GAL4 luciferase reporter</dna> .


By contrast , peritoneal fluid did not cause significant activation of PPAR-gamma/GAL4 constructs .

By contrast , peritoneal fluid did not cause significant activation of <dna>PPAR-gamma/GAL4 constructs</dna> .


The U937 cells transiently transfected with a PPAR response element luciferase reporter showed disease stage-dependent up-regulation when treated with peritoneal fluid from patients with endometriosis .

The <cell_line>U937 cells</cell_line> transiently transfected with a <dna>PPAR response element luciferase reporter</dna> showed disease stage-dependent up-regulation when treated with peritoneal fluid from patients with endometriosis .


Treatment with peritoneal fluid from healthy controls down-regulated PPAR response element transactivation .


We conclude that peritoneal fluid of endometriosis patients contains activators of PPAR-alpha that stimulate macrophage chemotaxis .

We conclude that peritoneal fluid of endometriosis patients contains activators of <protein>PPAR-alpha</protein> that stimulate macrophage chemotaxis .


Inhibitors of PPAR-alpha or activators of PPAR-gamma could be developed for the treatment of inflammation associated with endometriosis .

Inhibitors of <protein>PPAR-alpha</protein> or activators of <protein>PPAR-gamma</protein> could be developed for the treatment of inflammation associated with endometriosis .


Long-term-impaired expression of nuclear factor-kappa B and I kappa B alpha in peripheral blood mononuclear cells of trauma patients .

Long-term-impaired expression of <protein>nuclear factor-kappa B</protein> and <protein>I kappa B alpha</protein> in <cell_type>peripheral blood mononuclear cells</cell_type> of trauma patients .


Nuclear factor ( NF ) -kappa B expression and dimer characteristics were studied in peripheral blood mononuclear cells ( PBMCs ) of major-trauma patients and healthy controls .

<protein>Nuclear factor ( NF ) -kappa B</protein> expression and dimer characteristics were studied in <cell_type>peripheral blood mononuclear cells</cell_type> ( <cell_type>PBMCs</cell_type> ) of major-trauma patients and healthy controls .


Analysis of PBMCs on days 1 , 3 , 5 , and 10 after trauma revealed that expression of both p65p50 heterodimers and p50p50 homodimers was significantly reduced compared with that in controls .

Analysis of <cell_type>PBMCs</cell_type> on days 1 , 3 , 5 , and 10 after trauma revealed that expression of both <protein>p65p50 heterodimers</protein> and <protein>p50p50 homodimers</protein> was significantly reduced compared with that in controls .


In vitro lipopolysaccharide ( LPS ) stimulation of PBMCs induced NF-kappa B translocation .

In vitro lipopolysaccharide ( LPS ) stimulation of <cell_type>PBMCs</cell_type> induced NF-kappa B translocation .


However , throughout the survey , p65p50 activation remained significantly lower in trauma patients than in controls .


After LPS stimulation in vitro , the p65p50/p50p50 ratio was significantly lower in PBMCs from trauma patients than from healthy controls .

After LPS stimulation in vitro , the p65p50/p50p50 ratio was significantly lower in <cell_type>PBMCs</cell_type> from trauma patients than from healthy controls .


The ex vivo expression of I kappa B alpha was higher in PBMCs of controls than of trauma patients .

The ex vivo expression of <protein>I kappa B alpha</protein> was higher in <cell_type>PBMCs</cell_type> of controls than of trauma patients .


LPS did not induce I kappa B expression in PBMCs from trauma patients , but strong induction was obtained with staphylococci , suggesting that this defect is not universal and depends on the nature of the activating signal .

LPS did not induce I kappa B expression in <cell_type>PBMCs</cell_type> from trauma patients , but strong induction was obtained with staphylococci , suggesting that this defect is not universal and depends on the nature of the activating signal .


Although no direct correlation was found between levels of interleukin-10 or transforming growth factor-beta and NF-kappa B , these immunosuppressive cytokines were significantly elevated in trauma patients by 10 days after admission .

Although no direct correlation was found between levels of <protein>interleukin-10</protein> or <protein>transforming growth factor-beta</protein> and <protein>NF-kappa B</protein> , these <protein>immunosuppressive cytokines</protein> were significantly elevated in trauma patients by 10 days after admission .


The long-term low-basal and LPS-induced nuclear translocation of NF-kappa B recalled long-term immunoparalysis observed in patients with severe inflammatory stress such as trauma .

The long-term low-basal and LPS-induced nuclear translocation of <protein>NF-kappa B</protein> recalled long-term immunoparalysis observed in patients with severe inflammatory stress such as trauma .


Hepatic ischemia-reperfusion injury .


BACKGROUND : The morbidity associated with liver transplantation and major hepatic resections is partly a result of ischemia-reperfusion injury .


DATA SOURCES : The entire world literature on the subject was searched via Medline .


Keywords included reperfusion injury , transplantation , liver resection , nitric oxide , endothelin , cytokines , Kupffer cells , ischemic/ischaemic preconditioning , and nuclear factor-kappa B .

Keywords included reperfusion injury , transplantation , liver resection , nitric oxide , endothelin , <protein>cytokines</protein> , <cell_type>Kupffer cells</cell_type> , ischemic/ischaemic preconditioning , and <protein>nuclear factor-kappa B</protein> .


CONCLUSIONS : An imbalance between endothelin and nitric oxide levels results in failure of the hepatic microcirculation at the onset of reperfusion .


Activation of nuclear factor-kappa B in the liver promotes proinflammatory cytokine and adhesion molecule synthesis .

Activation of <protein>nuclear factor-kappa B</protein> in the liver promotes <protein>proinflammatory cytokine</protein> and <protein>adhesion molecule</protein> synthesis .


These result in oxygen-derived free radical production and neutrophil recruitment , further contributing to cellular injury .


Various therapeutic modalities acting on the above mediators have been successfully used to attenuate reperfusion injury in animal models of hepatic transplantation and resection .


Application of the knowledge gained from animal models of hepatic ischemia-reperfusion to the clinical setting will improve the outcome of hepatic surgery .


Down-regulation of IL-12 p40 gene in Plasmodium berghei-infected mice .

Down-regulation of <dna>IL-12 p40 gene</dna> in Plasmodium berghei-infected mice .


We analyzed the mechanism that causes suppression of IL-12 p40 gene induction during Plasmodium berghei infection .

We analyzed the mechanism that causes suppression of <dna>IL-12 p40 gene</dna> induction during Plasmodium berghei infection .


Although IL-12 together with IFN-gamma plays an important role in protection against pathogenic infection , the IL-12 p70 protein production of infected macrophages is lower than that by the uninfected macrophages .

Although <protein>IL-12</protein> together with <protein>IFN-gamma</protein> plays an important role in protection against pathogenic infection , the <protein>IL-12 p70 protein</protein> production of <cell_type>infected macrophages</cell_type> is lower than that by the <cell_type>uninfected macrophages</cell_type> .


We showed in the present study that the induction of IL-12 p40 gene but not IL-12 p35 gene in macrophages of P. berghei-infected mice was profoundly inhibited .

We showed in the present study that the induction of <dna>IL-12 p40 gene</dna> but not <dna>IL-12 p35 gene</dna> in <cell_type>macrophages</cell_type> of P. berghei-infected mice was profoundly inhibited .


The inhibition was induced by interaction with macrophages that had contacted with P. berghei-infected erythrocytes and was mediated by a soluble factor , IL-10 .

The inhibition was induced by interaction with <cell_type>macrophages</cell_type> that had contacted with <cell_type>P. berghei-infected erythrocytes</cell_type> and was mediated by a soluble factor , <protein>IL-10</protein> .


There was comparable activation of NF-kappaB in uninfected and infected cells .

There was comparable activation of <protein>NF-kappaB</protein> in <cell_type>uninfected and infected cells</cell_type> .


The induction of IFN-regulatory factor-1 gene was comparable in transcription level in uninfected and infected cells , while the unidentified complex formation of IFN-regulatory factor-1 was observed in infected cells .

The induction of <dna>IFN-regulatory factor-1 gene</dna> was comparable in transcription level in <cell_type>uninfected and infected cells</cell_type> , while the unidentified complex formation of <protein>IFN-regulatory factor-1</protein> was observed in <cell_type>infected cells</cell_type> .


Therefore , the inhibition of the IL-12 p40 gene induction appeared to be regulated at transcriptional regulation level of the gene .

Therefore , the inhibition of the <dna>IL-12 p40 gene</dna> induction appeared to be regulated at transcriptional regulation level of the gene .


The Friend of GATA proteins U-shaped , FOG-1 , and FOG-2 function as negative regulators of blood , heart , and eye development in Drosophila .

The <protein>Friend of GATA proteins</protein> U-shaped , <protein>FOG-1</protein> , and <protein>FOG-2</protein> function as negative regulators of blood , heart , and eye development in Drosophila .


Friend of GATA ( FOG ) proteins regulate GATA factor-activated gene transcription .

<protein>Friend of GATA ( FOG ) proteins</protein> regulate GATA factor-activated gene transcription .


During vertebrate hematopoiesis , FOG and GATA proteins cooperate to promote erythrocyte and megakaryocyte differentiation .

During vertebrate hematopoiesis , <protein>FOG and GATA proteins</protein> cooperate to promote erythrocyte and megakaryocyte differentiation .


The Drosophila FOG homologue U-shaped ( Ush ) is expressed similarly in the blood cell anlage during embryogenesis .

The <protein>Drosophila FOG homologue U-shaped</protein> ( <protein>Ush</protein> ) is expressed similarly in the blood cell anlage during embryogenesis .


During hematopoiesis , the acute myeloid leukemia 1 homologue Lozenge and Glial cells missing are required for the production of crystal cells and plasmatocytes , respectively .

During hematopoiesis , the acute myeloid leukemia 1 homologue <cell_type>Lozenge and Glial cells</cell_type> missing are required for the production of <cell_type>crystal cells</cell_type> and <cell_type>plasmatocytes</cell_type> , respectively .


However , additional factors have been predicted to control crystal cell proliferation .


In this report , we show that Ush is expressed in hemocyte precursors and plasmatocytes throughout embryogenesis and larval development , and the GATA factor Serpent is essential for Ush embryonic expression .

In this report , we show that <protein>Ush</protein> is expressed in <cell_type>hemocyte precursors</cell_type> and <cell_type>plasmatocytes</cell_type> throughout embryogenesis and larval development , and the <protein>GATA factor Serpent</protein> is essential for <protein>Ush</protein> embryonic expression .


Furthermore , loss of ush function results in an overproduction of crystal cells , whereas forced expression of Ush reduces this cell population .

Furthermore , loss of ush function results in an overproduction of <cell_type>crystal cells</cell_type> , whereas forced expression of <protein>Ush</protein> reduces this cell population .


Murine FOG-1 and FOG-2 also can repress crystal cell production , but a mutant version of FOG-2 lacking a conserved motif that binds the corepressor C-terminal binding protein fails to affect the cell lineage .

<protein>Murine FOG-1 and FOG-2</protein> also can repress crystal cell production , but a mutant version of <protein>FOG-2</protein> lacking a conserved motif that binds the <protein>corepressor C-terminal binding protein</protein> fails to affect the cell lineage .


The GATA factor Pannier ( Pnr ) is required for eye and heart development in Drosophila .

The <protein>GATA factor Pannier</protein> ( <protein>Pnr</protein> ) is required for eye and heart development in Drosophila .


When Ush , FOG-1 , FOG-2 , or mutant FOG-2 is coexpressed with Pnr during these developmental processes , severe eye and heart phenotypes result , consistent with a conserved negative regulation of Pnr function .

When <protein>Ush</protein> , <protein>FOG-1</protein> , <protein>FOG-2</protein> , or <protein>mutant FOG-2</protein> is coexpressed with <protein>Pnr</protein> during these developmental processes , severe eye and heart phenotypes result , consistent with a conserved negative regulation of <protein>Pnr</protein> function .


These results indicate that the fly and mouse FOG proteins function similarly in three distinct cellular contexts in Drosophila , but may use different mechanisms to regulate genetic events in blood vs . cardial or eye cell lineages

These results indicate that the fly and mouse <protein>FOG proteins</protein> function similarly in three distinct cellular contexts in Drosophila , but may use different mechanisms to regulate genetic events in blood vs . <cell_line>cardial or eye cell lineages</cell_line>


The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1 .

The <protein>RING finger protein</protein> <protein>Siah-1</protein> regulates the level of the <protein>transcriptional coactivator</protein> <protein>OBF-1</protein> .


The transcriptional coactivator OBF-1 , which interacts with Oct-1 and Oct-2 and the octamer site DNA , has been shown to be critical for development of a normal immune response and the formation of germinal centers in secondary lymphoid organs .

The <protein>transcriptional coactivator</protein> <protein>OBF-1</protein> , which interacts with <protein>Oct-1</protein> and <protein>Oct-2</protein> and the <dna>octamer site DNA</dna> , has been shown to be critical for development of a normal immune response and the formation of germinal centers in secondary lymphoid organs .


Here we have identified the RING finger protein Siah-1 as a protein interacting specifically with OBF-1 .

Here we have identified the <protein>RING finger protein</protein> <protein>Siah-1</protein> as a protein interacting specifically with <protein>OBF-1</protein> .


This interaction is mediated by the C-terminal part of Siah-1 and by residues in the N-terminus of OBF-1 , partly distinct from the residues required for formation of a complex with the Oct POU domains and the DNA .

This interaction is mediated by the <protein>C-terminal</protein> part of <protein>Siah-1</protein> and by residues in the <protein>N-terminus</protein> of <protein>OBF-1</protein> , partly distinct from the residues required for formation of a complex with the <protein>Oct POU domains</protein> and the DNA .


Interaction between Siah-1 and OBF-1 leads to downregulation of OBF-1 protein level but not mRNA , and to a corresponding reduction in octamer site-dependent transcription activation .

Interaction between <protein>Siah-1</protein> and <protein>OBF-1</protein> leads to downregulation of OBF-1 protein level but not mRNA , and to a corresponding reduction in octamer site-dependent transcription activation .


Inhibition of the ubiquitin-proteasome pathway in B cells leads to elevated levels of OBF-1 protein .

Inhibition of the ubiquitin-proteasome pathway in <cell_type>B cells</cell_type> leads to elevated levels of <protein>OBF-1 protein</protein> .


Furthermore , in immunized mice , OBF-1 protein amounts are dramatically increased in primary activated B cells , without concomitant increase in OBF-1 mRNA .

Furthermore , in immunized mice , <protein>OBF-1 protein</protein> amounts are dramatically increased in <cell_type>primary activated B cells</cell_type> , without concomitant increase in <rna>OBF-1 mRNA</rna> .


These data suggest that Siah-1 is part of a novel regulatory loop controlling the level of OBF-1 protein in B cells .

These data suggest that <protein>Siah-1</protein> is part of a novel regulatory loop controlling the level of <protein>OBF-1 protein</protein> in <cell_type>B cells</cell_type> .


The beta-catenin -- TCF-1 pathway ensures CD4 ( + ) CD8 ( + ) thymocyte survival .

The beta-catenin -- TCF-1 pathway ensures <cell_type>CD4 ( + ) CD8 ( + ) thymocyte</cell_type> survival .


The association of trans-acting T cell factors ( TCFs ) or lymphoid enhancer factor 1 ( LEF-1 ) with their coactivator beta-catenin mediates transient transcriptional responses to extracellular Wnt signals .

The association of <protein>trans-acting T cell factors</protein> ( <protein>TCFs</protein> ) or <protein>lymphoid enhancer factor 1</protein> ( <protein>LEF-1</protein> ) with their coactivator beta-catenin mediates transient transcriptional responses to extracellular Wnt signals .


We show here that T cell maturation depends on the presence of the beta-catenin -- binding domain in TCF-1 .

We show here that T cell maturation depends on the presence of the <protein>beta-catenin -- binding domain</protein> in <protein>TCF-1</protein> .


This domain is necessary to mediate the survival of immature CD4 ( + ) CD8 ( + ) double-positive ( DP ) thymocytes .

This domain is necessary to mediate the survival of immature <cell_type>CD4 ( + ) CD8 ( + ) double-positive ( DP ) thymocytes</cell_type> .


Accelerated spontaneous thymocyte death in the absence of TCF-1 correlates with aberrantly low expression of the anti-apoptotic protein Bcl-x ( L ) .

Accelerated spontaneous thymocyte death in the absence of <protein>TCF-1</protein> correlates with aberrantly low expression of the <protein>anti-apoptotic protein</protein> <protein>Bcl-x ( L )</protein> .


Increasing anti-apoptotic effectors in thymocytes by the use of a Bcl-2 transgene rescued TCF-1-deficient DP thymocytes from apoptosis .

Increasing anti-apoptotic effectors in <cell_type>thymocytes</cell_type> by the use of a <dna>Bcl-2 transgene</dna> rescued <cell_type>TCF-1-deficient DP thymocytes</cell_type> from apoptosis .


Thus , TCF-1 , upon association with beta-catenin , transiently ensures the survival of immature T cells , which enables them to generate and edit T cell receptor ( TCR ) alpha chains and attempt TCR -mediated positive selection .

Thus , <protein>TCF-1</protein> , upon association with beta-catenin , transiently ensures the survival of <cell_type>immature T cells</cell_type> , which enables them to generate and edit <protein>T cell receptor ( TCR ) alpha chains</protein> and attempt <protein>TCR</protein> -mediated positive selection .


TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma : therapeutic applications .

<protein>TRAIL/Apo2L ligand</protein> selectively induces apoptosis and overcomes drug resistance in multiple myeloma : therapeutic applications .


Multiple myeloma ( MM ) remains incurable and novel treatments are urgently needed .


Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor ( TNF ) -related apoptosis-inducing ligand/Apo2 ligand ( TRAIL/Apo2L ) in MM .

Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant <protein>tumor necrosis factor ( TNF ) -related apoptosis-inducing ligand/Apo2 ligand</protein> ( <protein>TRAIL/Apo2L</protein> ) in MM .


TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines , including cells sensitive or resistant to dexamethasone ( Dex ) , doxorubicin ( Dox ) , melphalan , and mitoxantrone .

<protein>TRAIL/Apo2L</protein> potently induced apoptosis of <cell_type>MM cells</cell_type> from patients and the majority of <cell_line>MM cell lines</cell_line> , including cells sensitive or resistant to dexamethasone ( Dex ) , doxorubicin ( Dox ) , melphalan , and mitoxantrone .


TRAIL/Apo2L also overcame the survival effect of interleukin 6 on MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors .

<protein>TRAIL/Apo2L</protein> also overcame the survival effect of <protein>interleukin 6</protein> on <cell_type>MM cells</cell_type> and did not affect the survival of <cell_type>peripheral blood and bone marrow mononuclear cells</cell_type> and <cell_type>purified B cells</cell_type> from healthy donors .


The status of the TRAIL receptors ( assessed by immunoblotting and flow cytometry ) could not predict TRAIL sensitivity of MM cells .

The status of the <protein>TRAIL receptors</protein> ( assessed by immunoblotting and flow cytometry ) could not predict TRAIL sensitivity of <cell_type>MM cells</cell_type> .


The anti-MM activity of TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with human MM cells ; TRAIL ( 500 microg intraperitoneally daily for 14 days ) was well tolerated and significantly suppressed the growth of plasmacytomas .

The anti-MM activity of <protein>TRAIL/Apo2L</protein> was confirmed in nu/xid/bg mice xenografted with <cell_type>human MM cells</cell_type> ; <protein>TRAIL</protein> ( 500 microg intraperitoneally daily for 14 days ) was well tolerated and significantly suppressed the growth of <cell_type>plasmacytomas</cell_type> .


Dox up-regulated the expression of the TRAIL receptor death receptor 5 ( DR5 ) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to , but also against those resistant to , Dex- or Dox-induced apoptosis .

Dox up-regulated the expression of the <protein>TRAIL receptor</protein> <protein>death receptor 5</protein> ( <protein>DR5</protein> ) and synergistically enhanced the effect of <protein>TRAIL</protein> not only against <cell_type>MM cells</cell_type> sensitive to , but also against those resistant to , Dex- or Dox-induced apoptosis .


Nuclear factor ( NF ) -kappaB inhibitors , such as SN50 ( a cell-permeable inhibitor of the nuclear translocation and transcriptional activity of NF-kappaB ) or the proteasome inhibitor PS-341 , enhanced the proapoptotic activity of TRAIL/Apo2L against TRAIL-sensitive MM cells , whereas SN50 reversed the TRAIL resistance of ARH-77 and IM-9 MM cells .

Nuclear factor ( NF ) -kappaB inhibitors , such as SN50 ( a cell-permeable inhibitor of the nuclear translocation and transcriptional activity of <protein>NF-kappaB</protein> ) or the proteasome inhibitor PS-341 , enhanced the proapoptotic activity of <protein>TRAIL/Apo2L</protein> against <cell_type>TRAIL-sensitive MM cells</cell_type> , whereas SN50 reversed the TRAIL resistance of <cell_type>ARH-77 and IM-9 MM cells</cell_type> .


Importantly , normal B lymphocytes were not sensitized to TRAIL by either Dox , SN50 , or PS-341 .

Importantly , <cell_type>normal B lymphocytes</cell_type> were not sensitized to <protein>TRAIL</protein> by either Dox , SN50 , or PS-341 .


These preclinical studies suggest that TRAIL/Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL -based treatment regimens to improve outcome in patients with MM .

These preclinical studies suggest that <protein>TRAIL/Apo2L</protein> can overcome conventional drug resistance and provide the basis for clinical trials of <protein>TRAIL</protein> -based treatment regimens to improve outcome in patients with MM .


( Blood. 2001 ; 98 : 795-804 )


CD28 costimulation is required not only to induce IL-12 receptor but also to render janus kinases/STAT4 responsive to IL-12 stimulation in TCR-triggered T cells .

<protein>CD28</protein> costimulation is required not only to induce <protein>IL-12 receptor</protein> but also to render <protein>janus kinases/STAT4</protein> responsive to <protein>IL-12</protein> stimulation in <cell_type>TCR-triggered T cells</cell_type> .


The activation of resting T cells for the acquisition of various functions depends on whether CD28 costimulatory signals are provided upon T cell receptor stimulation .

The activation of <cell_type>resting T cells</cell_type> for the acquisition of various functions depends on whether CD28 costimulatory signals are provided upon T cell receptor stimulation .


Here , we investigated how CD28 costimulation functions to allow TCR -triggered resting T cells to acquire IL-12 responsiveness .

Here , we investigated how CD28 costimulation functions to allow <protein>TCR</protein> -triggered <cell_type>resting T cells</cell_type> to acquire <protein>IL-12</protein> responsiveness .


When T cells are stimulated with low doses of anti-CD3 mAb , CD28 costimulation was required for the optimal levels of IL-12 receptor ( IL-12R ) expression .

When <cell_type>T cells</cell_type> are stimulated with low doses of <protein>anti-CD3 mAb</protein> , CD28 costimulation was required for the optimal levels of <protein>IL-12 receptor</protein> ( <protein>IL-12R</protein> ) expression .


However , stimulation of T cells with high doses of anti-CD3 alone induced comparable levels of IL-12R expression to those induced upon CD28 costimulation .

However , stimulation of <cell_type>T cells</cell_type> with high doses of <protein>anti-CD3</protein> alone induced comparable levels of <protein>IL-12R</protein> expression to those induced upon CD28 costimulation .


Nevertheless , there was a substantial difference in IL-12 responsiveness between these two groups of T cells : compared to anti-CD28-costimulated T cells , T cells that were not costimulated with anti-CD28 exhibited decreased levels of Janus kinases ( JAK ) JAK2/TYK2 and STAT4 phosphorylation and IFN-y production following IL-12 stimulation .

Nevertheless , there was a substantial difference in <protein>IL-12</protein> responsiveness between these two groups of <cell_type>T cells</cell_type> : compared to <cell_type>anti-CD28-costimulated T cells</cell_type> , <cell_type>T cells</cell_type> that were not costimulated with <protein>anti-CD28</protein> exhibited decreased levels of <protein>Janus kinases</protein> ( <protein>JAK</protein> ) <protein>JAK2/TYK2</protein> and <protein>STAT4</protein> phosphorylation and IFN-y production following <protein>IL-12</protein> stimulation .


Importantly , STAT6 phosphorylation following IL-4 stimulation was not decreased in anti-CD28-uncostimulated T cells .

Importantly , STAT6 phosphorylation following IL-4 stimulation was not decreased in <cell_type>anti-CD28-uncostimulated T cells</cell_type> .


These resutls indicate that CD28 costimulation not only contributes to up-regulating IL-12R expression but is also required to render JAKs/STAT4 responsive to IL-12 stimulation .

These resutls indicate that CD28 costimulation not only contributes to up-regulating <protein>IL-12R</protein> expression but is also required to render <protein>JAKs/STAT4</protein> responsive to <protein>IL-12</protein> stimulation .


Constitutively activated Akt-1 is vital for the survival of human monocyte-differentiated macrophages .

Constitutively activated <protein>Akt-1</protein> is vital for the survival of <cell_type>human monocyte-differentiated macrophages</cell_type> .


Role of Mcl-1 , independent of nuclear factor ( NF ) -kappaB , Bad , or caspase activation .

Role of <protein>Mcl-1</protein> , independent of <protein>nuclear factor ( NF ) -kappaB</protein> , <protein>Bad</protein> , or caspase activation .


Recent data from mice deficient for phosphatase and tensin homologue deleted from chromosome 10 or src homology 2 domain-containing 5 ' inositol phosphatase , phosphatases that negatively regulate the phosphatidylinositol 3-kinase ( PI3K ) pathway , revealed an increased number of macrophages in these animals , suggesting an essential role for the PI3K pathway for macro-phage survival .

Recent data from mice deficient for <protein>phosphatase</protein> and <dna>tensin homologue</dna> deleted from <dna>chromosome 10</dna> or <protein>src homology 2 domain-containing 5 ' inositol phosphatase</protein> , <protein>phosphatases</protein> that negatively regulate the <protein>phosphatidylinositol 3-kinase</protein> ( <protein>PI3K</protein> ) pathway , revealed an increased number of <cell_type>macrophages</cell_type> in these animals , suggesting an essential role for the <protein>PI3K</protein> pathway for <cell_type>macro-phage</cell_type> survival .


Here , we focused on the role of the PI3K-regulated serine/threonine kinase Akt-1 in modulating macrophage survival .

Here , we focused on the role of the <protein>PI3K-regulated serine/threonine kinase</protein> <protein>Akt-1</protein> in modulating <cell_type>macrophage</cell_type> survival .


Akt-1 was constitutively activated in human macrophages and addition of the PI3K inhibitor , LY294002 , suppressed the activation of Akt-1 and induced cell death .

<protein>Akt-1</protein> was constitutively activated in <cell_type>human macrophages</cell_type> and addition of the <protein>PI3K</protein> inhibitor , LY294002 , suppressed the activation of <protein>Akt-1</protein> and induced cell death .


Furthermore , suppression of Akt-1 by inhibition of PI3K or a dominant negative ( DN ) Akt-1 resulted in loss of mitochondrial transmembrane potential , activation of caspases-9 and -3 , and DNA fragmentation .

Furthermore , suppression of <protein>Akt-1</protein> by inhibition of <protein>PI3K</protein> or a <protein>dominant negative ( DN ) Akt-1</protein> resulted in loss of mitochondrial transmembrane potential , activation of <protein>caspases-9 and -3</protein> , and DNA fragmentation .


The effects of PI3K inhibition were reversed by the ectopic expression of constitutively activated Akt-1 or Bcl-x ( L ) .

The effects of <protein>PI3K</protein> inhibition were reversed by the ectopic expression of constitutively activated <protein>Akt-1</protein> or <protein>Bcl-x ( L )</protein> .


Inhibition of PI3K /Akt-1 pathway either by LY294002 or DN Akt-1 had no effect on the constitutive or inducible activation of nuclear factor ( NF ) -kappaB in human macrophages .

Inhibition of <protein>PI3K</protein> /Akt-1 pathway either by LY294002 or <protein>DN Akt-1</protein> had no effect on the constitutive or inducible activation of <protein>nuclear factor ( NF ) -kappaB</protein> in <cell_type>human macrophages</cell_type> .


However , after inhibition of the PI3K / Akt-1 pathway , a marked decrease in the expression of the antiapoptotic molecule Mcl-1 , but not other Bcl-2 family members was observed , and Mcl-1 rescued macrophages from LY294002-induced cell death .

However , after inhibition of the <protein>PI3K</protein> / <protein>Akt-1</protein> pathway , a marked decrease in the expression of the <protein>antiapoptotic molecule</protein> <protein>Mcl-1</protein> , but not other <protein>Bcl-2 family members</protein> was observed , and <protein>Mcl-1</protein> rescued <cell_type>macrophages</cell_type> from LY294002-induced cell death .


Further , inhibition of Mcl-1 by antisense oligonucleotides , also resulted in macrophage apoptosis .

Further , inhibition of <protein>Mcl-1</protein> by antisense oligonucleotides , also resulted in <cell_type>macrophage</cell_type> apoptosis .


Thus , our findings demonstrate that the constitutive activation of Akt-1 regulates macrophage survival through Mcl-1 , which is independent of caspases , NF-kappaB , or Bad .

Thus , our findings demonstrate that the constitutive activation of <protein>Akt-1</protein> regulates <cell_type>macrophage</cell_type> survival through <protein>Mcl-1</protein> , which is independent of <protein>caspases</protein> , <protein>NF-kappaB</protein> , or <protein>Bad</protein> .


GRbeta expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone .

GRbeta expression in <cell_type>nasal polyp inflammatory cells</cell_type> and its relationship to the anti-inflammatory effects of intranasal fluticasone .


BACKGROUND : Nasal polyposis disease is an inflammatory disorder with intense eosinophilic infiltration of respiratory mucosa that is often difficult to control with topical steroids .


Recent evidence suggests that overexpression of the glucocorticoid receptor splice variant GRbeta in inflammatory cells might contribute to steroid insensitivity in diseases such as asthma .

Recent evidence suggests that overexpression of the <protein>glucocorticoid receptor splice variant</protein> <protein>GRbeta</protein> in <cell_type>inflammatory cells</cell_type> might contribute to steroid insensitivity in diseases such as asthma .


OBJECTIVE : The purposes of this investigation were to determine whether nasal polyp ( NP ) inflammatory cells overexpress GRbeta and to examine whether GRbeta overexpression is associated with insensitivity to the potent topical steroid fluticasone propionate ( FP ) .

OBJECTIVE : The purposes of this investigation were to determine whether <cell_type>nasal polyp ( NP ) inflammatory cells</cell_type> overexpress <protein>GRbeta</protein> and to examine whether <protein>GRbeta</protein> overexpression is associated with insensitivity to the potent topical steroid fluticasone propionate ( FP ) .


METHODS : Biopsies were obtained from 10 subjects with NPs before and 4 weeks after treatment with intranasal FP .


Middle turbinates biopsies from 6 healthy , nonallergic subjects served as normal controls .


Biopsies were immunostained for inflammatory cell markers as well as GRbeta and probed for various cytokine mRNA .

Biopsies were immunostained for inflammatory cell markers as well as <protein>GRbeta</protein> and probed for various <rna>cytokine mRNA</rna> .


The anti-inflammatory response to FP was examined in relation to pretreatment levels of GRbeta expression .


RESULTS : The total numbers of inflammatory cells were increased in NPs .

RESULTS : The total numbers of <cell_type>inflammatory cells</cell_type> were increased in <cell_type>NPs</cell_type> .


The percentage of inflammatory cells expressing GRbeta was also increased ( 40.5 % +/- 19.2 % vs 16.1 % +/- 4.0 % , P =.009 ) .

The percentage of <cell_type>inflammatory cells</cell_type> expressing <protein>GRbeta</protein> was also increased ( 40.5 % +/- 19.2 % vs 16.1 % +/- 4.0 % , P =.009 ) .


GRbeta expression in NPs was almost exclusive to T lymphocytes , eosinophils , and macrophages .

<protein>GRbeta</protein> expression in <cell_type>NPs</cell_type> was almost exclusive to <cell_type>T lymphocytes</cell_type> , <cell_type>eosinophils</cell_type> , and <cell_type>macrophages</cell_type> .


An inverse correlation was observed between the baseline inflammatory cell GRbeta expression and the reduction after FP treatment in EG2-positive eosinophils , CD4-positive T lymphocytes , endothelial VCAM-1 expression , and IL-4 mRNA-positive cells .

An inverse correlation was observed between the baseline inflammatory cell <protein>GRbeta</protein> expression and the reduction after FP treatment in <cell_type>EG2-positive eosinophils</cell_type> , <cell_type>CD4-positive T lymphocytes</cell_type> , endothelial <protein>VCAM-1</protein> expression , and <cell_type>IL-4 mRNA-positive cells</cell_type> .


NPs that were `` FP-insensitive '' in terms of suppression of eosinophil numbers ( major basic protein -positive ) had a significantly greater percentage of GRbeta-positive inflammatory cells , a higher ratio of GRbeta-positive/GRalpha-positive cells , and increased numbers of GRbeta-positive eosinophils and macrophages in comparison with those that were `` FP-sensitive. ''

<cell_type>NPs</cell_type> that were `` FP-insensitive '' in terms of suppression of <cell_type>eosinophil</cell_type> numbers ( <protein>major basic protein</protein> -positive ) had a significantly greater percentage of <cell_type>GRbeta-positive inflammatory cells</cell_type> , a higher ratio of <cell_type>GRbeta-positive/GRalpha-positive cells</cell_type> , and increased numbers of <cell_type>GRbeta-positive eosinophils</cell_type> and <cell_type>macrophages</cell_type> in comparison with those that were `` FP-sensitive. ''


`` FP-insensitive '' NPs also demonstrated a higher percentage of IL-5-positive inflammatory cells expressing GRbeta before and after FP treatment .

<cell_type>`` FP-insensitive '' NPs</cell_type> also demonstrated a higher percentage of <cell_type>IL-5-positive inflammatory cells</cell_type> expressing <protein>GRbeta</protein> before and after FP treatment .


CONCLUSION : GRbeta expression appears to be a marker of steroid insensitivity in NPs .

CONCLUSION : <protein>GRbeta</protein> expression appears to be a marker of steroid insensitivity in <cell_type>NPs</cell_type> .


Expression of GRbeta by NP inflammatory cells , particularly T cells and eosinophils , might render them resistant to suppression by topical steroids and thereby contribute to persistent NP inflammation .

Expression of <protein>GRbeta</protein> by <cell_type>NP inflammatory cells</cell_type> , particularly <cell_type>T cells</cell_type> and <cell_type>eosinophils</cell_type> , might render them resistant to suppression by topical steroids and thereby contribute to persistent <cell_type>NP</cell_type> inflammation .


Transcriptional regulation of galectin-10 ( eosinophil Charcot-Leyden crystal protein ) : a GC box ( -44 to -50 ) controls butyric acid induction of gene expression .

Transcriptional regulation of <protein>galectin-10</protein> ( <protein>eosinophil Charcot-Leyden crystal protein</protein> ) : a <dna>GC box</dna> ( -44 to -50 ) controls butyric acid induction of gene expression .


Galectin-10 ( gal-10 , also known as Charcot-Leyden crystal protein ) is a member of the galectin family of beta-galactoside binding proteins that is expressed uniquely in eosinophilic and basophilic leukocytes .

<protein>Galectin-10</protein> ( <protein>gal-10</protein> , also known as <protein>Charcot-Leyden crystal protein</protein> ) is a member of the <protein>galectin family</protein> of <protein>beta-galactoside binding proteins</protein> that is expressed uniquely in <cell_type>eosinophilic and basophilic leukocytes</cell_type> .


To gain a better understanding of galectin gene expression , we present an analysis of the transcriptional regulation of the gene encoding gal-10 .

To gain a better understanding of galectin gene expression , we present an analysis of the transcriptional regulation of the gene encoding <protein>gal-10</protein> .


Analysis of the minimal promoter revealed nine consensus-binding sites for transcription factors , including several that are also found in the minimal promoters of galectins -1 , -2 , and -3 .

Analysis of the <dna>minimal promoter</dna> revealed nine <dna>consensus-binding sites</dna> for <protein>transcription factors</protein> , including several that are also found in the <dna>minimal promoters</dna> of <dna>galectins -1 , -2 , and -3</dna> .


The decrease in gal-10 promoter activity after disruption of either the GC box ( -44 to -50 ) or the Oct site ( -255 to -261 ) suggests that these sites , along with the previously characterized GATA and EoTF sites , are necessary for full promoter activity .

The decrease in gal-10 promoter activity after disruption of either the <dna>GC box</dna> ( -44 to -50 ) or the <dna>Oct site</dna> ( -255 to -261 ) suggests that these sites , along with the previously characterized <dna>GATA and EoTF sites</dna> , are necessary for full promoter activity .


By supershift analysis , we demonstrate binding of the transcription factors Sp1 and Oct1 to the consensus GC box and the Oct site , respectively .

By supershift analysis , we demonstrate binding of the <protein>transcription factors</protein> <protein>Sp1</protein> and <protein>Oct1</protein> to the <dna>consensus GC box</dna> and the <dna>Oct site</dna> , respectively .


Similar to gal-1 , gal-10 expression is induced by butyric acid , an effect that is lost upon ablation of the GC box .

Similar to <dna>gal-1</dna> , gal-10 expression is induced by butyric acid , an effect that is lost upon ablation of the <dna>GC box</dna> .


Additionally , we demonstrate AML3 binding to the consensus AML site and YY1 binding to the Inr sequence , both elements functioning as silencers in the gal-10 promoter .

Additionally , we demonstrate AML3 binding to the <dna>consensus AML site</dna> and <protein>YY1 binding</protein> to the <dna>Inr sequence</dna> , both elements functioning as silencers in the <dna>gal-10 promoter</dna> .


Tumour-stromal interactions .


Role of the stroma in mammary development .


Mammary development depends on branching morphogenesis , namely the bifurcation and extension of ductal growth points ( end buds ) and secretory lobules into a more or less fatty stroma .


Because breast carcinomas are overwhelmingly ductal in origin , this review focuses on stromal influences guiding postnatal ductal development and there is only the briefest account of the role of embryonic stroma ( mesenchyme ) .


The stroma as the necessary target for endocrine mammogens and the source of stimulatory growth factors is described and the importance of mammary epithelium-induced modifications of the periductal stroma is emphasized .


Evidence is presented that if they are to grow , end buds must condition proximal fatty stroma by recruiting white blood cells as well as inducing stromal cell division and , possibly , estrogen receptors .

Evidence is presented that if they are to grow , end buds must condition proximal fatty stroma by recruiting <cell_type>white blood cells</cell_type> as well as inducing stromal cell division and , possibly , <protein>estrogen receptors</protein> .


The induction of a fibrous stromal tunic around the end bud is described and its likely role as a complex ductal morphogen is discussed ; a possible role in growth inhibition is also considered .


Although the signals governing fibrotic induction , ductal morphogenesis , and growth inhibition are unknown , a role for transforming growth factor-beta is highly likely and is discussed .

Although the signals governing fibrotic induction , ductal morphogenesis , and growth inhibition are unknown , a role for transforming <protein>growth factor-beta</protein> is highly likely and is discussed .


Finally , a need for new conceptual and experimental approaches to understanding stromal-epithelial signaling is discussed .


Adipophilin is a sensitive marker for lipid loading in human blood monocytes .

<protein>Adipophilin</protein> is a sensitive marker for lipid loading in <cell_type>human blood monocytes</cell_type> .


Adipophilin , a marker of lipid accumulation initially described in adipocytes , was recently shown to be induced in macrophage foam cells .

<protein>Adipophilin</protein> , a marker of lipid accumulation initially described in <cell_type>adipocytes</cell_type> , was recently shown to be induced in <cell_type>macrophage foam cells</cell_type> .


We found that even freshly isolated blood monocytes express adipophilin and that the amount of adipophilin protein is variable in monocytes from different healthy individuals .

We found that even <cell_type>freshly isolated blood monocytes</cell_type> express <protein>adipophilin</protein> and that the amount of <protein>adipophilin protein</protein> is variable in <cell_type>monocytes</cell_type> from different healthy individuals .


However , the physiological expression of adipophilin does not correlate with the levels of free fatty acids , cholesterylesters or free cholesterol .

However , the physiological expression of <protein>adipophilin</protein> does not correlate with the levels of free fatty acids , cholesterylesters or free cholesterol .


Enzymatically modified low-density lipoprotein ( E-LDL ) induces rapid foam cell formation in monocytes and upregulates adipophilin mRNA and protein within 2 h of incubation .

<protein>Enzymatically modified low-density lipoprotein</protein> ( <protein>E-LDL</protein> ) induces rapid foam cell formation in <cell_type>monocytes</cell_type> and upregulates <protein>adipophilin</protein> mRNA and protein within 2 h of incubation .


This rapid induction of adipophilin is accompanied by a significant increase of free fatty acids in monocytes incubated with E-LDL .

This rapid induction of <protein>adipophilin</protein> is accompanied by a significant increase of free fatty acids in <cell_type>monocytes</cell_type> incubated with <protein>E-LDL</protein> .


Adipophilin facilitates the uptake of free fatty acids , and here we demonstrate that free fatty acids increase is related to the early upregulation of adipophilin expression in blood monocytes .

<protein>Adipophilin</protein> facilitates the uptake of free fatty acids , and here we demonstrate that free fatty acids increase is related to the early upregulation of adipophilin expression in <cell_type>blood monocytes</cell_type> .


Fatty acids are ligands for peroxisome proliferator-activated receptor-gamma ( PPARgamma ) , and the upregulation of adipophilin mRNA by PPARgamma agonists like 15d-PGJ ( 2 ) and ciglitazone indicates that PPARgamma may mediate the induction of adipophilin expression in human blood monocytes .

Fatty acids are ligands for <protein>peroxisome proliferator-activated receptor-gamma</protein> ( <protein>PPARgamma</protein> ) , and the upregulation of <rna>adipophilin mRNA</rna> by <protein>PPARgamma</protein> agonists like 15d-PGJ ( 2 ) and ciglitazone indicates that <protein>PPARgamma</protein> may mediate the induction of adipophilin expression in <cell_type>human blood monocytes</cell_type> .


Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell-specific promoter .

Constitutive expression of <dna>MHC class II genes</dna> in <cell_line>melanoma cell lines</cell_line> results from the transcription of <dna>class II transactivator</dna> abnormally initiated from its <dna>B cell-specific promoter</dna> .


In melanoma cell lines , two different patterns of MHC class II expression have been described , either an IFN gamma-inducible expression of HLA-DR and HLA-DP , with a faint or null expression of HLA-DQ , resembling that described for melanocytes , or a constitutive expression , i.e. , IFN-gamma independent , of all three HLA-D isotypes .

In <cell_line>melanoma cell lines</cell_line> , two different patterns of MHC class II expression have been described , either an IFN gamma-inducible expression of <dna>HLA-DR</dna> and <dna>HLA-DP</dna> , with a faint or null expression of <dna>HLA-DQ</dna> , resembling that described for <cell_type>melanocytes</cell_type> , or a constitutive expression , i.e. , IFN-gamma independent , of all three <dna>HLA-D isotypes</dna> .


As this latter phenotype has been associated with a more rapid progression of melanoma tumors , we have analyzed in different melanoma cell lines the molecular mechanisms leading to this abnormal pattern of MHC class II expression .

As this latter phenotype has been associated with a more rapid progression of melanoma tumors , we have analyzed in different <cell_line>melanoma cell lines</cell_line> the molecular mechanisms leading to this abnormal pattern of MHC class II expression .


In agreement with the evidence of a coordinate transcription of the HLA-D genes in these cell lines , we have shown the constitutive expression of CIITA ( class II transactivator ) transcripts , CIITA being known as the master switch of MHC class II expression .

In agreement with the evidence of a coordinate transcription of the <dna>HLA-D genes</dna> in these cell lines , we have shown the constitutive expression of <rna>CIITA ( class II transactivator ) transcripts</rna> , <protein>CIITA</protein> being known as the master switch of MHC class II expression .


Unexpectedly , these transcripts initiate from promoter III of the CIITA gene , a promoter that is mainly used constitutively in B lymphocytes .

Unexpectedly , these transcripts initiate from <dna>promoter III</dna> of the <dna>CIITA gene</dna> , a promoter that is mainly used constitutively in <cell_type>B lymphocytes</cell_type> .


This expression was further shown to occur through factor ( s ) acting on the enhancer located upstream of CIITA promoter III , which was previously described in epithelioid cells as an IFN-gamma-response sequence .

This expression was further shown to occur through factor ( s ) acting on the enhancer located upstream of <dna>CIITA promoter III</dna> , which was previously described in <cell_type>epithelioid cells</cell_type> as an IFN-gamma-response sequence .


The hypothesis of a general abnormality of the IFN-gamma transduction pathway was dismissed .


Constitutive transcription of CIITA from promoter III having been observed in unrelated melanoma cell lines , we propose the hypothesis that this phenomenon might not be a random event , but could be linked to the neoplasic state of the melanoma cells

Constitutive transcription of <dna>CIITA</dna> from <dna>promoter III</dna> having been observed in unrelated <cell_line>melanoma cell lines</cell_line> , we propose the hypothesis that this phenomenon might not be a random event , but could be linked to the neoplasic state of the <cell_type>melanoma cells</cell_type>


Caspase -mediated calcineurin activation contributes to IL-2 release during T cell activation .

<protein>Caspase</protein> -mediated calcineurin activation contributes to <protein>IL-2</protein> release during T cell activation .


Calcineurin , a Ca ( 2+ ) /calmodulin-dependent Ser/Thr phosphatase ( protein phosphatase 2B ) , plays a critical role in IL-2 production during T cell activation .

<protein>Calcineurin</protein> , a <protein>Ca ( 2+ ) /calmodulin-dependent Ser/Thr phosphatase ( protein phosphatase 2B )</protein> , plays a critical role in IL-2 production during T cell activation .


It has been previously reported that IL-2 release in activated Jurkat T requires caspase-like activity ( Posmantur et al. ( 1998 ) Exp. Cell. Res. 244 , 302-309 ) .

It has been previously reported that <protein>IL-2</protein> release in activated <cell_line>Jurkat T</cell_line> requires caspase-like activity ( Posmantur et al. ( 1998 ) Exp. Cell. Res. 244 , 302-309 ) .


We report here that the 60-kDa catalytic subunit of calcineurin A ( Cn A ) was partially cleaved to a 45-kDa form in phytohemagglutinin A ( PHA ) or phorbol ester + ionomycin ( P + I ) -activated Jurkat cells .

We report here that the <protein>60-kDa catalytic subunit</protein> of <protein>calcineurin A</protein> ( <protein>Cn A</protein> ) was partially cleaved to a <protein>45-kDa</protein> form in phytohemagglutinin A ( PHA ) or phorbol ester + ionomycin ( P + I ) -activated <cell_line>Jurkat cells</cell_line> .


In parallel , proteolytic activation of upstream caspases ( caspase-8 and -9 ) as well as effector caspase-3 was also observed .

In parallel , proteolytic activation of upstream <protein>caspases</protein> ( caspase-8 and -9 ) as well as <protein>effector caspase-3</protein> was also observed .


Cn A cleavage was caspase mediated , since it was inhibitable by pan-caspase inhibitor Cbz-Asp-CH ( 2 ) OC ( O ) -2 , 6-dichlorobenzene ( Z-D-DCB ) .

<protein>Cn A</protein> cleavage was caspase mediated , since it was inhibitable by pan-caspase inhibitor Cbz-Asp-CH ( 2 ) OC ( O ) -2 , 6-dichlorobenzene ( Z-D-DCB ) .


Cn A cleavage was also observed when purified calcineurin was digested in vitro with caspase-3 .

<protein>Cn A</protein> cleavage was also observed when purified <protein>calcineurin</protein> was digested in vitro with <protein>caspase-3</protein> .


Truncated Cn A was associated with enhanced phosphatase activity and reduced calmodulin sensitivity .

<protein>Truncated Cn A</protein> was associated with enhanced phosphatase activity and reduced calmodulin sensitivity .


Furthermore , in PHA or P + I-activated Jurkat cells , dephosphorylation of calcineurin substrate NFATc ( a transcription factor known to be involved in transactivation of the IL-2 gene ) , was also suppressed by Z-D-DCB .

Furthermore , in PHA or P + I-activated <cell_line>Jurkat cells</cell_line> , dephosphorylation of <protein>calcineurin</protein> substrate <protein>NFATc</protein> ( a <protein>transcription factor</protein> known to be involved in transactivation of the <dna>IL-2 gene</dna> ) , was also suppressed by Z-D-DCB .


Taken together , our results suggest that caspase-mediated cleavage of Cn A contributes to IL-2 production during T cell activation .

Taken together , our results suggest that caspase-mediated cleavage of <protein>Cn A</protein> contributes to IL-2 production during T cell activation .


Copyright 2001 Academic Press .


Maturation of human dendritic cells as sulfasalazine target .

Maturation of <cell_type>human dendritic cells</cell_type> as sulfasalazine target .


AIM : Sulfasalazine , a nonsteroidal anti-inflammatory drug , is effective in treating some autoimmune diseases , but its mechanism of action is unclear .


To determine whether dendritic cells could be a possible target of the drug , we studied the effects of sulfasalazine and its metabolites , aminosalicylate and sulfapyridine , on in vitro maturation ( terminal differentiation ) of human myeloid dendritic cells .

To determine whether <cell_type>dendritic cells</cell_type> could be a possible target of the drug , we studied the effects of sulfasalazine and its metabolites , aminosalicylate and sulfapyridine , on in vitro maturation ( terminal differentiation ) of <cell_type>human myeloid dendritic cells</cell_type> .


METHODS : We prepared immature dendritic cells by incubating CD14-positive cells in the presence of granulocyte- macrophage colony-stimulating factor and interleukin ( IL ) -4 .

METHODS : We prepared <cell_type>immature dendritic cells</cell_type> by incubating <cell_type>CD14-positive cells</cell_type> in the presence of <protein>granulocyte- macrophage colony-stimulating factor</protein> and <protein>interleukin ( IL ) -4</protein> .


The cells were matured by addition of tumor necrosis factor ( TNF ) -a , IL-1 beta , and prostaglandin E2 in the presence of sulfasalazine or its metabolites -- aminosalicylate and sulfapyridine , or their combinations .

The cells were matured by addition of <protein>tumor necrosis factor ( TNF ) -a</protein> , <protein>IL-1 beta</protein> , and <protein>prostaglandin E2</protein> in the presence of sulfasalazine or its metabolites -- aminosalicylate and sulfapyridine , or their combinations .


We quantified the effect of drugs on the dendritic cell characteristics , such as stimulation of autologous and allogeneic pan-T cell proliferation , surface marker phenotype , IL-12 p40 subunit secretion , and activation of nuclear transcription factor ( NF ) -kappa B .

We quantified the effect of drugs on the dendritic cell characteristics , such as stimulation of autologous and allogeneic pan-T cell proliferation , surface marker phenotype , IL-12 p40 subunit secretion , and activation of <protein>nuclear transcription factor ( NF ) -kappa B</protein> .


RESULTS : Dendritic cells treated with sulfasalazine ( 1.25 micromol/L or 2.5 micromol/L ) could not stimulate T cells ( p < 0.028 , two-sided paired t-test ) .

RESULTS : <cell_type>Dendritic cells</cell_type> treated with sulfasalazine ( 1.25 micromol/L or 2.5 micromol/L ) could not stimulate <cell_type>T cells</cell_type> ( p < 0.028 , two-sided paired t-test ) .


In distinction to drug-free maturing dendritic cells , 2.5 micromol/L sulfasalazine upregulated the levels of CD14 and CD68 and downregulated the levels of CD40 , CD80 , and CD83 ( for all CD markers , p < 0.03 for difference between measurements in the absence and the presence of sulfasalazine ) .

In distinction to drug-free maturing <cell_type>dendritic cells</cell_type> , 2.5 micromol/L sulfasalazine upregulated the levels of <protein>CD14</protein> and <protein>CD68</protein> and downregulated the levels of <protein>CD40</protein> , <protein>CD80</protein> , and <protein>CD83</protein> ( for all CD markers , p < 0.03 for difference between measurements in the absence and the presence of sulfasalazine ) .


From concentration-dependent changes in CD83 expression , we found an apparent ID50 > > 1.5 micromol/L sulfasalazine .


The apparent ID50 value for aminosalicylate-inhibited maturation was 4 micromol/L .


Sulfapyridine had no effect .


At 1.25 micromol/L , sulfasalazine largely inhibited NF-kB activation in dendritic cells .

At 1.25 micromol/L , sulfasalazine largely inhibited NF-kB activation in <cell_type>dendritic cells</cell_type> .


CONCLUSION : Maturing human dendritic cells are hundred-fold more sensitive to sulfasalazine than T cells and NK cells and the most sensitive human cells described so far .

CONCLUSION : <cell_type>Maturing human dendritic cells</cell_type> are hundred-fold more sensitive to sulfasalazine than <cell_type>T cells</cell_type> and <cell_type>NK cells</cell_type> and the most sensitive human cells described so far .


Thus , dendritic cell maturation is an important target of sulfasalazine .


Because of the role of dendritic cells in ( auto ) immunity , inhibition of their maturation might provide a target for further optimization of sulfasalazine therapy .

Because of the role of <cell_type>dendritic cells</cell_type> in ( auto ) immunity , inhibition of their maturation might provide a target for further optimization of sulfasalazine therapy .


Defective function of the proteasome in autoimmunity : involvement of impaired NF-kappaB activation .

Defective function of the <protein>proteasome</protein> in autoimmunity : involvement of impaired NF-kappaB activation .


Type 1 diabetes ( also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes ) is usually caused by T cell-mediated autoimmunity , with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells .

Type 1 diabetes ( also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes ) is usually caused by T cell-mediated autoimmunity , with a prediabetic state characterized by the production of <protein>autoantibodies</protein> specific for proteins expressed by <cell_type>pancreatic beta cells</cell_type> .