Up-regulation of RAR ( alpha ) and PML-RAR gene expression by IFN ( alpha ) is accompanied by a strong potentiation in the induction of 2 retinoid-dependent granulocytic markers , i.e. , granulocyte-colony-stimulating factor receptor mRNA and leukocyte alkaline phosphatase .

Up-regulation of <protein>RAR ( alpha )</protein> and <protein>PML-RAR</protein> gene expression by <protein>IFN ( alpha )</protein> is accompanied by a strong potentiation in the induction of 2 <protein>retinoid-dependent granulocytic markers</protein> , i.e. , <rna>granulocyte-colony-stimulating factor receptor mRNA</rna> and <protein>leukocyte alkaline phosphatase</protein> .


However , IFN ( alpha ) does not have any effects on the retinoid-dependent regulation of the myeloid surface markers CD11b and CD33 .

However , <protein>IFN ( alpha )</protein> does not have any effects on the retinoid-dependent regulation of the <protein>myeloid surface markers</protein> <protein>CD11b</protein> and <protein>CD33</protein> .


The IFN -dependent increase in RAR ( alpha ) levels and the enhancing effect of the cytokine on retinoid-dependent granulocytic markers expression may be a characteristic of PML-RAR positive cells , since the phenomena are not observed in HL-60 promyelocytes .

The <protein>IFN</protein> -dependent increase in <protein>RAR ( alpha )</protein> levels and the enhancing effect of the <protein>cytokine</protein> on <protein>retinoid-dependent granulocytic markers</protein> expression may be a characteristic of <cell_line>PML-RAR positive cells</cell_line> , since the phenomena are not observed in <cell_line>HL-60 promyelocytes</cell_line> .


Interferons as well as retinoids inhibit the growth of NB4 cells , although the 2 classes of compounds do not significantly interact in terms of anti-proliferative activity .

<protein>Interferons</protein> as well as retinoids inhibit the growth of <cell_line>NB4 cells</cell_line> , although the 2 classes of compounds do not significantly interact in terms of anti-proliferative activity .


These results suggest the possible use of combinations between IFNs and retinoic acid in the cyto-differentiating treatment of APL patients .

These results suggest the possible use of combinations between <protein>IFNs</protein> and retinoic acid in the cyto-differentiating treatment of APL patients .


Modulatory effects of glucocorticoids and catecholamines on human interleukin -12 and interleukin -10 production : clinical implications .

Modulatory effects of glucocorticoids and catecholamines on human <protein>interleukin</protein> -12 and <protein>interleukin</protein> -10 production : clinical implications .


Interleukin-12 ( IL-12 ) is a key inducer of differentiation of uncommitted T helper ( TH ) cells toward the TH1 phenotype , which regulates cellular immunity , whereas IL-10 inhibits TH1 functions and potentiates TH2-regulated responses ( i.e. , humoral immunity ) .

<protein>Interleukin-12</protein> ( <protein>IL-12</protein> ) is a key inducer of differentiation of <cell_type>uncommitted T helper ( TH ) cells</cell_type> toward the TH1 phenotype , which regulates cellular immunity , whereas <protein>IL-10</protein> inhibits TH1 functions and potentiates TH2-regulated responses ( i.e. , humoral immunity ) .


To examine the potential effects of stress on TH1/TH2 balance , we studied the ability of three prototype stress hormones-dexamethasone ( a synthetic glucocorticoid ) and the catecholamines norepinephrine and epinephrine-to alter the production of IL-12 ( p70 ) and IL-10 induced by bacterial lipopolysaccharide ( LPS ) in human whole blood .

To examine the potential effects of stress on TH1/TH2 balance , we studied the ability of three prototype stress hormones-dexamethasone ( a synthetic glucocorticoid ) and the catecholamines norepinephrine and epinephrine-to alter the production of <protein>IL-12</protein> ( <protein>p70</protein> ) and <protein>IL-10</protein> induced by bacterial lipopolysaccharide ( LPS ) in human whole blood .


Dexamethasone inhibited LPS-induced bioactive IL-12 production in a dose-dependent fashion and at physiologically relevant concentrations ; it had no effect on IL-10 secretion .

Dexamethasone inhibited LPS-induced bioactive <protein>IL-12</protein> production in a dose-dependent fashion and at physiologically relevant concentrations ; it had no effect on <protein>IL-10</protein> secretion .


The glucocorticoid-induced reduction of IL-12 production was antagonized by RU 486 , a glucocorticoid-receptor antagonist , suggesting that it was mediated by the glucocorticoid receptor .

The glucocorticoid-induced reduction of <protein>IL-12</protein> production was antagonized by RU 486 , a glucocorticoid-receptor antagonist , suggesting that it was mediated by the glucocorticoid receptor .


Norepinephrine and epinephrine also suppressed IL-12 production in a dose-dependent fashion and at physiological concentrations ; both catecholamines , however , dose-dependently increased the production of IL-10 .

Norepinephrine and epinephrine also suppressed <protein>IL-12</protein> production in a dose-dependent fashion and at physiological concentrations ; both catecholamines , however , dose-dependently increased the production of <protein>IL-10</protein> .


The effects of either catecholamine on IL-12 or IL-10 secretion were blocked completely by propranolol , a beta-adrenoreceptor antagonist , indicating that they were mediated by the beta-adrenergic receptor .

The effects of either catecholamine on <protein>IL-12</protein> or <protein>IL-10</protein> secretion were blocked completely by propranolol , a beta-adrenoreceptor antagonist , indicating that they were mediated by the <protein>beta-adrenergic receptor</protein> .


These findings suggest that the central nervous system may regulate IL-12 and IL-10 secretion and , hence , TH1/TH2 balance via the peripheral end-effectors of the stress system .


Thus , stress may cause a selective suppression of TH1 functions and a shift toward a TH2 cytokine pattern rather than generalized TH suppression .

Thus , stress may cause a selective suppression of TH1 functions and a shift toward a <protein>TH2 cytokine</protein> pattern rather than generalized TH suppression .


The TH1-to-TH2 shift may be responsible for the stress-induced susceptibility of the organism to certain infections .


Through the same or a reciprocal mechanism , states associated with chronic hyperactivity or hypoactivity of the stress system might influence the susceptibility of an individual to certain autoimmune , allergic , infectious , or neoplastic diseases .


Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional activator NF-kappa B .

Activation of <cell_type>human monocytic cells</cell_type> by <protein>Treponema pallidum and Borrelia burgdorferi lipoproteins</protein> and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional activator <protein>NF-kappa B</protein> .


There is increasing evidence that lipoproteins of Treponema pallidum and Borrelia burgdorferi are key inflammatory mediators during syphilis and Lyme disease .

There is increasing evidence that <protein>lipoproteins</protein> of Treponema pallidum and Borrelia burgdorferi are key inflammatory mediators during syphilis and Lyme disease .


A principal objective of the present study was to identify more precisely similarities and divergences among lipopolysaccharide ( LPS ) - and lipoprotein-lipopeptide-induced immune cell signaling events .


Like LPS , purified native B. burgdorferi OspA and synthetic analogs of OspA , OspB , and two T. pallidum lipoproteins ( Tpp47 and Tpp17 ) all induced NF-kappa B translocation in THP-1 human monocytoid cells .

Like LPS , <protein>purified native B. burgdorferi OspA</protein> and synthetic analogs of <protein>OspA</protein> , <protein>OspB</protein> , and two <protein>T. pallidum lipoproteins</protein> ( <protein>Tpp47</protein> and <protein>Tpp17</protein> ) all induced <protein>NF-kappa B</protein> translocation in <cell_type>THP-1 human monocytoid cells</cell_type> .


Acylation of OspA and the synthetic peptides was requisite for cell activation .

Acylation of <protein>OspA</protein> and the synthetic peptides was requisite for cell activation .


Polymyxin B abrogated only the response to LPS .


By using 70Z/3-derived pre-B-cell lines either lacking or expressing human CD14 ( the LPS receptor ) , it was observed that expression of human CD14 imparted responsiveness to LPS but not to OspA or spirochetal lipopeptides ( assessed by induction of NF-kappa B and expression of surface immunoglobulin M ) .

By using <cell_line>70Z/3-derived pre-B-cell lines</cell_line> either lacking or expressing <protein>human CD14</protein> ( the <protein>LPS receptor</protein> ) , it was observed that expression of <protein>human CD14</protein> imparted responsiveness to LPS but not to <protein>OspA</protein> or <protein>spirochetal lipopeptides</protein> ( assessed by induction of <protein>NF-kappa B</protein> and expression of <protein>surface immunoglobulin M</protein> ) .


Finally , the biological relevance of the observation that T. pallidum lipoproteins -lipopeptides induce both NF-kappa B and cytokine production in monocytes was supported by the ability of the synthetic analogs to promote human immunodeficiency virus replication in chronically infected U1 monocytoid cells ; these observations also suggest a potential mechanism whereby a syphilitic chancre can serve as a cofactor for human immunodeficiency virus transmission .

Finally , the biological relevance of the observation that <protein>T. pallidum lipoproteins</protein> -lipopeptides induce both <protein>NF-kappa B</protein> and <protein>cytokine</protein> production in <cell_type>monocytes</cell_type> was supported by the ability of the synthetic analogs to promote human immunodeficiency virus replication in chronically infected U1 monocytoid cells ; these observations also suggest a potential mechanism whereby a syphilitic chancre can serve as a cofactor for human immunodeficiency virus transmission .


The combined data lend additional support to the proposal that spirochetal lipoproteins and LPS initiate monocyte activation via different cell surface events but that the signaling pathways ultimately converge to produce qualitatively similar cellular responses .

The combined data lend additional support to the proposal that <protein>spirochetal lipoproteins</protein> and LPS initiate monocyte activation via different cell surface events but that the signaling pathways ultimately converge to produce qualitatively similar cellular responses .


LYSP100 -associated nuclear domains ( LANDs ) : description of a new class of subnuclear structures and their relationship to PML nuclear bodies .

<protein>LYSP100</protein> -associated nuclear domains ( LANDs ) : description of a new class of subnuclear structures and their relationship to PML nuclear bodies .


The PML gene is fused to the retinoic acid receptor alpha ( RAR alpha ) gene in t ( 15 ; 17 ) acute promyelocytic leukemia ( APL ) , creating a PML-RAR alpha fusion oncoprotein .

The <dna>PML gene</dna> is fused to the <dna>retinoic acid receptor alpha ( RAR alpha ) gene</dna> in t ( 15 ; 17 ) acute promyelocytic leukemia ( APL ) , creating a <protein>PML-RAR alpha fusion oncoprotein</protein> .


The PML gene product has been localized to subnuclear dot-like structures variously termed PODs , ND10s , Kr bodies , or PML nuclear bodies ( PML NBs ) .

The <protein>PML gene product</protein> has been localized to <cell_line>subnuclear dot-like structures</cell_line> variously termed PODs , ND10s , Kr bodies , or PML nuclear bodies ( PML NBs ) .


The present study describes the cloning of a lymphoid-restricted gene , LYSP100 , that is homologous to another protein that localizes to PML NBs , SP100 .

The present study describes the cloning of a <dna>lymphoid-restricted gene</dna> , <dna>LYSP100</dna> , that is homologous to another protein that localizes to PML NBs , <protein>SP100</protein> .


In addition to SP100 homology regions , one LYSP100 cDNA isoform contains a bromodomain and a PHD/TTC domain , which are present in a variety of transcriptional regulatory proteins .

In addition to <dna>SP100 homology regions</dna> , one <dna>LYSP100 cDNA isoform</dna> contains a <protein>bromodomain</protein> and a <protein>PHD/TTC domain</protein> , which are present in a variety of <protein>transcriptional regulatory proteins</protein> .


By immunofluorescence , LYSP100 was localized to nuclear dots that were surprisingly largely nonoverlapping with PML NBs .

By immunofluorescence , <dna>LYSP100</dna> was localized to nuclear dots that were surprisingly largely nonoverlapping with PML NBs .


However , a minority of LYSP100 nuclear dots exactly colocalized with PML and SP100 .

However , a minority of <dna>LYSP100</dna> nuclear dots exactly colocalized with <cell_type>PML</cell_type> and <protein>SP100</protein> .


We term the LYSP100 structures `` LANDs , '' for LYSP100 -associated nuclear domains .

We term the <dna>LYSP100</dna> structures `` LANDs , '' for <dna>LYSP100</dna> -associated nuclear domains .


Although LYSP100 is expressed only in lymphoid cells , LANDs could be visualized in HeLa cells by transfection of a LYSP100 cDNA .

Although <dna>LYSP100</dna> is expressed only in <cell_type>lymphoid cells</cell_type> , LANDs could be visualized in <cell_line>HeLa cells</cell_line> by transfection of a <dna>LYSP100 cDNA</dna> .


Immunoelectron microscopy revealed LANDs to be globular , electron-dense structures morphologically distinct from the annular structures characteristic of PML NBs .


LANDs were most often found in the nucleoplasm , but were also found at the nuclear membrane and in the cytoplasm , suggesting that these structures may traffic between the cytoplasm and the nucleus .


By double-immunogold labeling of PML and LYSP100 , some LANDs were shown to contain both PML and LYSP100 .

By double-immunogold labeling of <cell_type>PML</cell_type> and <dna>LYSP100</dna> , some LANDs were shown to contain both <cell_type>PML</cell_type> and <dna>LYSP100</dna> .


Thus , PML is localized to a second subnuclear domain that is morphologically and biochemically distinct from PML NBs .

Thus , <cell_type>PML</cell_type> is localized to a second subnuclear domain that is morphologically and biochemically distinct from <cell_type>PML</cell_type> NBs .


Transcriptional control of steroid-regulated apoptosis in murine thymoma cells .

Transcriptional control of steroid-regulated apoptosis in <cell_type>murine thymoma cells</cell_type> .


Early studies in murine T cell lines indicated that transcriptional transactivation functions encoded in the glucocorticoid receptor ( GR ) N-terminal domain are required for glucocorticoid-mediated apoptosis .

Early studies in murine <cell_line>T cell lines</cell_line> indicated that transcriptional transactivation functions encoded in the <protein>glucocorticoid receptor ( GR ) N-terminal domain</protein> are required for glucocorticoid-mediated apoptosis .


However , more recent studies in human T cell lines have suggested that the N-terminal domain is not necessary for steroid-regulated apoptosis and that GR -mediated transrepression may be the more critical mechanism .

However , more recent studies in <cell_line>human T cell lines</cell_line> have suggested that the <protein>N-terminal domain</protein> is not necessary for steroid-regulated apoptosis and that <protein>GR</protein> -mediated transrepression may be the more critical mechanism .


To better understand the contribution of the GR N-terminal transactivation domain in mediating murine thymocyte apoptosis , we stably transfected GR , GR variants , and the androgen receptor ( AR ) into receptor-negative S49 murine thymoma cells .

To better understand the contribution of the <protein>GR N-terminal transactivation domain</protein> in mediating murine thymocyte apoptosis , we stably transfected <protein>GR</protein> , <protein>GR variants</protein> , and the <protein>androgen receptor</protein> ( <protein>AR</protein> ) into <cell_line>receptor-negative S49 murine thymoma cells</cell_line> .


GR expression levels were shown to be rate-limiting for initiating the apoptotic pathway , and a positive correlation between steroid sensitivity and GR -mediated induction of an integrated mouse mammary tumor virus ( MMTV ) LTR reporter gene was observed .

<protein>GR</protein> expression levels were shown to be rate-limiting for initiating the apoptotic pathway , and a positive correlation between steroid sensitivity and <protein>GR</protein> -mediated induction of an integrated <dna>mouse mammary tumor virus ( MMTV ) LTR reporter gene</dna> was observed .


Analysis of GR chimeric receptors containing the potent VP16 and E1A viral transactivation domains in place of the GR N terminus revealed that even low level expression of these receptors resulted in both enhanced steroid sensitivity and MMTV induction , thus supporting a role for transactivation in apoptosis .

Analysis of <protein>GR chimeric receptors</protein> containing the potent <dna>VP16 and E1A viral transactivation domains</dna> in place of the <protein>GR N terminus</protein> revealed that even low level expression of these receptors resulted in both enhanced steroid sensitivity and MMTV induction , thus supporting a role for transactivation in apoptosis .


In contrast , we found that AR can initiate apoptosis in S49 cells after treatment with 5 alpha-dihydrotestosterone , despite its relative inability to induce high level expression of MMTV .

In contrast , we found that <protein>AR</protein> can initiate apoptosis in <cell_line>S49 cells</cell_line> after treatment with 5 alpha-dihydrotestosterone , despite its relative inability to induce high level expression of MMTV .


To investigate this further , we examined the steroid-regulated expression of an endogenous thymocyte-specific gene called GIG18 .

To investigate this further , we examined the steroid-regulated expression of an endogenous <dna>thymocyte-specific gene</dna> called <dna>GIG18</dna> .


We found that GIG18 was rapidly induced to comparable levels by both AR and GR , demonstrating that AR can indeed function as a transcriptional activator in S49 cells and , moreover , that GIG18 induction may be a marker of early apoptotic events in steroid-treated cells .

We found that <dna>GIG18</dna> was rapidly induced to comparable levels by both <protein>AR</protein> and <protein>GR</protein> , demonstrating that <protein>AR</protein> can indeed function as a transcriptional activator in <cell_line>S49 cells</cell_line> and , moreover , that <dna>GIG18</dna> induction may be a marker of early apoptotic events in steroid-treated cells .


Taken together , these results support our conclusion that transcriptional transactivation is a necessary signaling component of S49 cell apoptosis , although an additional role for GR -mediated transrepression can not be excluded .

Taken together , these results support our conclusion that transcriptional transactivation is a necessary signaling component of S49 cell apoptosis , although an additional role for <protein>GR</protein> -mediated transrepression can not be excluded .


Multiple p21ras effector pathways regulate nuclear factor of activated T cells .

Multiple <protein>p21ras</protein> effector pathways regulate nuclear factor of <cell_type>activated T cells</cell_type> .


The transcription factor , Nuclear Factor of Activated T cells ( NFAT ) is a major target for p21ras and calcium signalling pathways in the IL-2 gene and is induced by p21ras signals acting in synergy with calcium /calcineurin signals .

The <protein>transcription factor</protein> , <protein>Nuclear Factor of Activated T cells</protein> ( <protein>NFAT</protein> ) is a major target for <protein>p21ras</protein> and calcium signalling pathways in the <dna>IL-2 gene</dna> and is induced by <protein>p21ras</protein> signals acting in synergy with calcium <protein>/calcineurin</protein> signals .


One p21ras effector pathway involves the MAP kinase ERK-2 , and we have examined its role in NFAT regulation .

One <protein>p21ras</protein> effector pathway involves the <protein>MAP kinase</protein> <protein>ERK-2</protein> , and we have examined its role in <protein>NFAT</protein> regulation .


Expression of dominant negative MAPKK-1 prevents NFAT induction .

Expression of <protein>dominant negative MAPKK-1</protein> prevents <protein>NFAT</protein> induction .


Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1 , but does not substitute for activated p21ras and synergize with calcium /calcineurin signals to induce NFAT .

Constitutively active <protein>MAPKK-1</protein> fully activates <protein>ERK-2</protein> and the <protein>transcription factor</protein> <protein>Elk-1</protein> , but does not substitute for activated <protein>p21ras</protein> and synergize with calcium <protein>/calcineurin</protein> signals to induce <protein>NFAT</protein> .


Expression of dominant negative N17Rac also prevents TCR and p21ras activation of NFAT , but without interfering with the ERK-2 pathway .

Expression of <protein>dominant negative N17Rac</protein> also prevents <protein>TCR</protein> and <protein>p21ras</protein> activation of <protein>NFAT</protein> , but without interfering with the <protein>ERK-2</protein> pathway .


The transcriptional activity of the NFAT binding site is mediated by a complex comprising a member of the NFAT group and AP-1 family proteins .

The transcriptional activity of the <dna>NFAT binding site</dna> is mediated by a complex comprising a member of the <protein>NFAT</protein> group and <protein>AP-1 family proteins</protein> .


The induction of AP-1 by p21ras also requires Rac-1 function .

The induction of <protein>AP-1</protein> by <protein>p21ras</protein> also requires <protein>Rac-1</protein> function .


Activated Rac-1 could mimic activated p21ras to induce AP-1 but not to induce NFAT .

<protein>Activated Rac-1</protein> could mimic <protein>activated p21ras</protein> to induce <protein>AP-1</protein> but not to induce <protein>NFAT</protein> .


Moreover , the combination of activated MAPKK-1 and Rac-1 could not substitute for activated p21ras and synergize with calcium signals to induce NFAT .

Moreover , the combination of activated <protein>MAPKK-1</protein> and <protein>Rac-1</protein> could not substitute for activated <protein>p21ras</protein> and synergize with calcium signals to induce <protein>NFAT</protein> .


Thus , p21ras regulation of NFAT in T cells requires the activity of multiple effector pathways including those regulated by MAPKK-1 /ERK-2 and Rac-1 .

Thus , <protein>p21ras</protein> regulation of <protein>NFAT</protein> in <cell_type>T cells</cell_type> requires the activity of multiple effector pathways including those regulated by <protein>MAPKK-1</protein> <protein>/ERK-2</protein> and <protein>Rac-1</protein> .


Retinoid differentiation therapy in promyelocytic leukemia .


Acute promyelocytic leukemia ( APL ) is a specific type of acute myeloid leukemia characterized by the morphology of the blast cells , a specific t ( 15 ; 17 ) translocation , and risks of definite coagulopathy .

Acute promyelocytic leukemia ( APL ) is a specific type of acute myeloid leukemia characterized by the morphology of the <cell_type>blast cells</cell_type> , a specific t ( 15 ; 17 ) translocation , and risks of definite coagulopathy .


Recently this leukemia was further characterized by an exquisite sensitivity to all-trans retinoic acid 's differentiation effect and the production of a fusion gene altering the gene of RARalpha and a novel gene PML .

Recently this leukemia was further characterized by an exquisite sensitivity to all-trans retinoic acid 's differentiation effect and the production of a <dna>fusion gene</dna> altering the gene of <protein>RARalpha</protein> and a <dna>novel gene PML</dna> .


In vivo differentiation therapy with retinoids in APL patients follows strict guidelines related both to the APL cell and the biodisposal of all-trans retinoic acid .


Differential utilization of Janus kinase -signal transducer activator of transcription signaling pathways in the stimulation of human natural killer cells by IL-2 , IL-12 , and IFN-alpha .

Differential utilization of <protein>Janus kinase</protein> -signal transducer activator of transcription signaling pathways in the stimulation of <cell_type>human natural killer cells</cell_type> by <protein>IL-2</protein> , <protein>IL-12</protein> , and <protein>IFN-alpha</protein> .


IL-2- , IL-12- , and IFN-alpha-mediated signaling pathways were analyzed in primary NK cells and in the NK3.3 cell line .

IL-2- , IL-12- , and IFN-alpha-mediated signaling pathways were analyzed in <cell_type>primary NK cells</cell_type> and in the <cell_line>NK3.3 cell line</cell_line> .


Gel mobility shift and immunoprecipitation analyses revealed that in addition to activating STAT3 ( signal transducer and activator of transcription-3 ) and STAT5 , IL-2 induced tyrosine and serine phosphorylation of STAT1 alpha , which formed IFN-gamma-activated sequence-binding complexes by itself and with STAT3 .

Gel mobility shift and immunoprecipitation analyses revealed that in addition to activating <protein>STAT3</protein> ( <protein>signal transducer and activator of transcription-3</protein> ) and <protein>STAT5</protein> , <protein>IL-2</protein> induced tyrosine and serine phosphorylation of <protein>STAT1 alpha</protein> , which formed <protein>IFN-gamma-activated sequence-binding complexes</protein> by itself and with <protein>STAT3</protein> .


Although IL-2 and IFN-alpha activated STAT1 alpha and STAT5 , IL-2 predominantly activated STAT5 , while IFN-alpha predominantly activated STAT1 alpha .

Although <protein>IL-2</protein> and <protein>IFN-alpha</protein> activated <protein>STAT1 alpha</protein> and <protein>STAT5</protein> , <protein>IL-2</protein> predominantly activated <protein>STAT5</protein> , while <protein>IFN-alpha</protein> predominantly activated <protein>STAT1 alpha</protein> .


IL-2 induced less STAT1 alpha activation and IFN-alpha induced greater STAT5 activation in NK3.3 cells compared with preactivated primary NK cells .

<protein>IL-2</protein> induced less <protein>STAT1 alpha</protein> activation and <protein>IFN-alpha</protein> induced greater <protein>STAT5</protein> activation in <cell_line>NK3.3 cells</cell_line> compared with <cell_line>preactivated primary NK cells</cell_line> .


In NK3.3 cells , IL-2 induced comparable formation of c-fos promoter sis-inducible element IFN-gamma-activated sequence-binding complexes containing STAT3 alone with complexes containing STAT3 and STAT1 alpha , while in preactivated primary NK cells , it preferentially induced complexes containing STAT3 and STAT1 alpha .

In <cell_line>NK3.3 cells</cell_line> , <protein>IL-2</protein> induced comparable formation of <protein>c-fos promoter sis-inducible element IFN-gamma-activated sequence-binding complexes</protein> containing <protein>STAT3</protein> alone with complexes containing <protein>STAT3</protein> and <protein>STAT1 alpha</protein> , while in <cell_line>preactivated primary NK cells</cell_line> , it preferentially induced complexes containing <protein>STAT3</protein> and <protein>STAT1 alpha</protein> .


Thus , signaling in NK3.3 cells is not always identical with that in primary NK cells .

Thus , signaling in <cell_line>NK3.3 cells</cell_line> is not always identical with that in <cell_type>primary NK cells</cell_type> .


In contrast to IL-2 and IFN-alpha , IL-12 induced strong tyrosine phosphorylation of STAT4 and variable weak phosphorylation of STAT3 .

In contrast to <protein>IL-2</protein> and <protein>IFN-alpha</protein> , <protein>IL-12</protein> induced strong tyrosine phosphorylation of <protein>STAT4</protein> and variable weak phosphorylation of <protein>STAT3</protein> .


However , supershift analyses using the c-fos promoter sis-inducible element probe showed that IL-12 activated STAT4 , STAT1 alpha , and STAT3 , and induced complexes containing STAT4 only , STAT4 with STAT1 alpha , STAT3 with STAT1 alpha , or STAT1 alpha only in preactivated primary NK cells .

However , supershift analyses using the <dna>c-fos promoter sis-inducible element probe</dna> showed that <protein>IL-12</protein> activated <protein>STAT4</protein> , <protein>STAT1 alpha</protein> , and <protein>STAT3</protein> , and induced complexes containing <protein>STAT4</protein> only , <protein>STAT4</protein> with <protein>STAT1 alpha</protein> , <protein>STAT3</protein> with <protein>STAT1 alpha</protein> , or <protein>STAT1 alpha</protein> only in <cell_line>preactivated primary NK cells</cell_line> .


STAT1 alpha activation by IL-12 correlated with increased phosphorylation of serine , but not tyrosine .

<protein>STAT1 alpha</protein> activation by <protein>IL-12</protein> correlated with increased phosphorylation of serine , but not tyrosine .


Finally , IL-2 induced tyrosine phosphorylation of JAK1 and JAK3 , while IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells .

Finally , <protein>IL-2</protein> induced tyrosine phosphorylation of <protein>JAK1</protein> and <protein>JAK3</protein> , while <protein>IL-12</protein> induced phosphorylation of <protein>JAK2</protein> and <protein>TYK2</protein> in both <cell_line>preactivated primary NK and NK3.3 cells</cell_line> .


Differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2 , IL-12 , and IFN-alpha may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells .

Differential phosphorylation and consequent differential activation of both separate and overlapping <protein>STAT proteins</protein> by <protein>IL-2</protein> , <protein>IL-12</protein> , and <protein>IFN-alpha</protein> may provide a molecular basis for the similarities and differences in the actions of these <protein>cytokines</protein> on <cell_type>NK cells</cell_type> .


The suppression of T cell function and NF ( kappa ) B expression by serine protease inhibitors is blocked by N-acetylcysteine .

The suppression of <cell_type>T cell</cell_type> function and <protein>NF ( kappa ) B</protein> expression by serine protease inhibitors is blocked by N-acetylcysteine .


Direct evidence that N-acetylcysteine ( NAC ) enhances the immune response of peripheral blood T cells at the level of NF ( kappa ) B is presented .

Direct evidence that N-acetylcysteine ( NAC ) enhances the immune response of <cell_type>peripheral blood T cells</cell_type> at the level of <protein>NF ( kappa ) B</protein> is presented .


In addition , NAC blocks the suppression of T cell mitogenesis and cytokine production by protease inhibitors such as N-tosylphenylalanine chloromethyl ketone ( TPCK ) .

In addition , NAC blocks the suppression of T cell mitogenesis and <protein>cytokine</protein> production by protease inhibitors such as N-tosylphenylalanine chloromethyl ketone ( TPCK ) .


The proliferative responses of purified CD4+ or CD8+ T cells are suppressed more strongly by TPCK when anti-CD28 rather than the phorbol ester PMA is used as the mitogenic coactivator .

The proliferative responses of <cell_type>purified CD4+ or CD8+ T cells</cell_type> are suppressed more strongly by TPCK when <protein>anti-CD28</protein> rather than the phorbol ester PMA is used as the mitogenic <protein>coactivator</protein> .


Cytokine ( IL-2 , IL-6 , INF-gamma ) production is inhibited 95-100 % by concentrations of TPCK that totally suppress the mitogenesis of CD4+ or CD8+ cells .

<protein>Cytokine</protein> ( <protein>IL-2</protein> , <protein>IL-6</protein> , <protein>INF-gamma</protein> ) production is inhibited 95-100 % by concentrations of TPCK that totally suppress the mitogenesis of <cell_type>CD4+ or CD8+ cells</cell_type> .


Using electrophoretic mobility shift assays , we find that TPCK virtually abolishes ( to less than 1 % ) the levels of NF ( kappa ) B ( but not Oct-1 ) found in nuclear and whole cell extracts of activated T cells .

Using electrophoretic mobility shift assays , we find that TPCK virtually abolishes ( to less than 1 % ) the levels of <protein>NF ( kappa ) B</protein> ( but not <protein>Oct-1</protein> ) found in nuclear and whole cell extracts of <cell_type>activated T cells</cell_type> .


Strikingly , the immunosuppressive effects of TPCK are blocked when T cells are pretreated for 15 min with 5 mM NAC .

Strikingly , the immunosuppressive effects of TPCK are blocked when <cell_type>T cells</cell_type> are pretreated for 15 min with 5 mM NAC .


NAC not only blocks the effect of TPCK but enhances mitogenesis and cytokine production ( > 2.5-fold in some cases ) upon activation of unsuppressed T cells .

NAC not only blocks the effect of TPCK but enhances mitogenesis and <protein>cytokine</protein> production ( > 2.5-fold in some cases ) upon activation of <cell_type>unsuppressed T cells</cell_type> .


Our data support the notion that NF ( kappa ) B and I ( kappa ) B proteases play obligate roles in T cell activation and mitogenesis , roles that are enhanced significantly by NAC .

Our data support the notion that <protein>NF ( kappa ) B</protein> and <protein>I ( kappa ) B proteases</protein> play obligate roles in T cell activation and mitogenesis , roles that are enhanced significantly by NAC .


Signaling by IL-2 and related cytokines : JAKs , STATs , and relationship to immunodeficiency .

Signaling by <protein>IL-2</protein> and related <protein>cytokines</protein> : <protein>JAKs</protein> , <protein>STATs</protein> , and relationship to immunodeficiency .


Cytokines that bind to the interleukin-2 ( IL-2 ) receptor common gamma chain ( gamma c ) , including IL-2 , IL-4 , IL-7 , IL-9 , and IL-15 , are important for the growth and differentiation of T and B lymphocytes , natural killer cells , macrophages , and monoctyes .

<protein>Cytokines</protein> that bind to the <protein>interleukin-2 ( IL-2 ) receptor common gamma chain</protein> ( <protein>gamma c</protein> ) , including <protein>IL-2</protein> , <protein>IL-4</protein> , <protein>IL-7</protein> , <protein>IL-9</protein> , and <protein>IL-15</protein> , are important for the growth and differentiation of <cell_type>T and B lymphocytes</cell_type> , <cell_type>natural killer cells</cell_type> , <cell_type>macrophages</cell_type> , and <cell_type>monoctyes</cell_type> .


These cytokines have overlapping biological effects that in part result from the use of the shared receptor subunit gamma c .

These <protein>cytokines</protein> have overlapping biological effects that in part result from the use of the <protein>shared receptor subunit gamma c</protein> .


Recently it has become clear that these cytokines activate a number of important intracellular signaling molecules , including the Janus kinases JAK1 and JAK3 and members of the transcription factor family of signal transducers and activators of transcription ( STATs ) .

Recently it has become clear that these <protein>cytokines</protein> activate a number of important <protein>intracellular signaling molecules</protein> , including the <protein>Janus kinases</protein> <protein>JAK1</protein> and <protein>JAK3</protein> and members of the <protein>transcription factor family</protein> of <protein>signal transducers</protein> and <protein>activators of transcription</protein> ( <protein>STATs</protein> ) .


The discovery of these signaling pathways has led to important new insights into their role in lymphocyte maturation , as it has emerged that mutations in the genes encoding both gamma c and JAK3 result in similar forms of severe combined immunodeficiency ( SCID ) .

The discovery of these signaling pathways has led to important new insights into their role in lymphocyte maturation , as it has emerged that mutations in the genes encoding both <protein>gamma c</protein> and <protein>JAK3</protein> result in similar forms of severe combined immunodeficiency ( SCID ) .


In this review we examine the structure and function of cytokine receptors and the signaling pathways involved in their regulation of gene expression .

In this review we examine the structure and function of <protein>cytokine receptors</protein> and the signaling pathways involved in their regulation of gene expression .


Furthermore , we discuss recent advances that have led to a better understanding of how cytokines elicit intracellular responses , as well as their role in normal lymphoid development .

Furthermore , we discuss recent advances that have led to a better understanding of how <protein>cytokines</protein> elicit intracellular responses , as well as their role in normal lymphoid development .


Cytomegalovirus modulates interleukin-6 gene expression .

Cytomegalovirus modulates <dna>interleukin-6 gene</dna> expression .


Complications after lung transplantation include the development of rejection and an increased incidence of infection , particularly with cytomegalovirus ( CMV ) .


Several recent studies have suggested that interleukin ( IL ) -6 may be used to detect both infection and rejection after lung transplantation .


In addition , IL-6 may play a role in the development of bronchiolitis obliterans after transplantation .

In addition , <protein>IL-6</protein> may play a role in the development of bronchiolitis obliterans after transplantation .


Because CMV is also associated with the development of bronchiolitis obliterans after transplantation , we determined whether CMV induces IL-6 gene expression .

Because CMV is also associated with the development of bronchiolitis obliterans after transplantation , we determined whether CMV induces <protein>IL-6</protein> gene expression .


We demonstrated that CMV infection increased both IL-6 protein and mRNA in peripheral blood mononuclear cells .

We demonstrated that CMV infection increased both <protein>IL-6 protein</protein> and <rna>mRNA</rna> in <cell_type>peripheral blood mononuclear cells</cell_type> .


We also demonstrated that the CMV immediate early 1 gene product increased expression of the IL-6 promoter .

We also demonstrated that the <protein>CMV immediate early 1 gene product</protein> increased expression of the <dna>IL-6 promoter</dna> .


This effect of the CMV immediate early 1 gene product was dependent upon the presence of specific transcription factor binding sites in the IL-6 promoter .

This effect of the <protein>CMV immediate early 1 gene product</protein> was dependent upon the presence of specific <dna>transcription factor binding sites</dna> in the <dna>IL-6 promoter</dna> .


These studies demonstrate that CMV may be an important cofactor in the development of rejection and infection after transplantation through its effects on IL-6 .

These studies demonstrate that CMV may be an important cofactor in the development of rejection and infection after transplantation through its effects on <protein>IL-6</protein> .


Vitamin D3- and retinoic acid-induced monocytic differentiation : interactions between the endogenous vitamin D3 receptor , retinoic acid receptors , and retinoid X receptors in U-937 cells .

Vitamin D3- and retinoic acid-induced monocytic differentiation : interactions between the <protein>endogenous vitamin D3 receptor</protein> , <protein>retinoic acid receptors</protein> , and <protein>retinoid X receptors</protein> in <cell_line>U-937 cells</cell_line> .


Retinoic acid ( RA ) and 1 , 25 alpha-dihydroxycholecalciferol ( VitD3 ) are potent regulators of hematopoletic differentiation .


Yet , little is known as to how the RA and VitD3 receptor network operates in hematopoietic cells , and whether receptor interactions can explain the interplay between the RA -and VitD3-signaling pathways during differentiation .

Yet , little is known as to how the <protein>RA and VitD3 receptor network</protein> operates in <cell_type>hematopoietic cells</cell_type> , and whether receptor interactions can explain the interplay between the RA -and VitD3-signaling pathways during differentiation .


Therefore , we analyzed the expression , DNA binding , and transcriptional activity of the endogenous RA and VitD3 receptors [ retinoic acid receptors ( RARs ) , retinoid X receptors ( RXRs ) , and VitD3 receptor ( VDR ) ] in the U-937 cell line , in which RA and VitD3 induce distinct monocytic differentiation pathways .

Therefore , we analyzed the expression , DNA binding , and transcriptional activity of the <protein>endogenous RA and VitD3 receptors</protein> [ <protein>retinoic acid receptors</protein> ( <protein>RARs</protein> ) , <protein>retinoid X receptors</protein> ( <protein>RXRs</protein> ) , and <protein>VitD3 receptor</protein> ( <protein>VDR</protein> ) ] in the <cell_line>U-937 cell line</cell_line> , in which RA and VitD3 induce distinct monocytic differentiation pathways .


VitD3 induction resulted in the formation of VDR/RXR DNA-binding complexes on both VitD3 response elements and RA response elements ( RAREs ) .

VitD3 induction resulted in the formation of <protein>VDR/RXR DNA-binding complexes</protein> on both <dna>VitD3 response elements</dna> and <dna>RA response elements</dna> ( <dna>RAREs</dna> ) .


However , transcriptional activation was only observed from a VitD3 response element-driven reporter construct .

However , transcriptional activation was only observed from a <dna>VitD3 response element-driven reporter construct</dna> .


Several DNA-binding complexes were detected on RAREs in undifferentiated cells .

Several <protein>DNA-binding complexes</protein> were detected on <dna>RAREs</dna> in <cell_type>undifferentiated cells</cell_type> .


Stimulation by RA resulted in increased RAR beta /RXR DNA binding , activated RARE -dependent transcription , and increased expression of RAR-beta .

Stimulation by RA resulted in increased <protein>RAR beta</protein> <protein>/RXR</protein> DNA binding , activated <dna>RARE</dna> -dependent transcription , and increased expression of <protein>RAR-beta</protein> .


Concomitant stimulation by VitD3 inhibited the RA-stimulated formation of RAR beta/RXR heterodimers , favoring VDR /RXR binding to the RARE .

Concomitant stimulation by VitD3 inhibited the RA-stimulated formation of <protein>RAR beta/RXR heterodimers</protein> , favoring <protein>VDR</protein> <protein>/RXR</protein> binding to the <dna>RARE</dna> .


Also , VitD3 inhibited the expression of CD23 and CD49f , characteristic markers of retinoid-induced U-937 cell differentiation .

Also , VitD3 inhibited the expression of <protein>CD23</protein> and <protein>CD49f</protein> , characteristic markers of retinoid-induced <cell_line>U-937 cell</cell_line> differentiation .


In contrast , neither the RA-stimulated , RARE -mediated transcription nor the induced RAR-beta expression was suppressed by VitD3 , suggesting that VitD3 selectively inhibited the retinoid-induced differentiation program but not the RARE -mediated signal .

In contrast , neither the RA-stimulated , <dna>RARE</dna> -mediated transcription nor the induced <protein>RAR-beta</protein> expression was suppressed by VitD3 , suggesting that VitD3 selectively inhibited the retinoid-induced differentiation program but not the <dna>RARE</dna> -mediated signal .


These results demonstrate a complex role for VitD3 in modifying the retinoid differentiation pathway and may have implications for differentiation-inducing therapy of hematopoietic tumors .


The human T-cell leukemia virus type 1 posttranscriptional trans-activator Rex contains a nuclear export signal .

The <protein>human T-cell leukemia virus type 1 posttranscriptional trans-activator</protein> <protein>Rex</protein> contains a <protein>nuclear export signal</protein> .


The Rex protein of human T-cell leukemia virus type 1 is required for the nuclear export of unspliced viral mRNA and , therefore , for virus replication .

The <protein>Rex protein</protein> of human T-cell leukemia virus type 1 is required for the nuclear export of <rna>unspliced viral mRNA</rna> and , therefore , for virus replication .


In this manuscript , we demonstrate that Rex shuttles between the nucleus and the cytoplasm and that its activation domain constitutes a nuclear export signal that specifies efficient transport to the cytoplasm .

In this manuscript , we demonstrate that <protein>Rex</protein> shuttles between the nucleus and the cytoplasm and that its <protein>activation domain</protein> constitutes a <protein>nuclear export signal</protein> that specifies efficient transport to the cytoplasm .


These findings are consistent with a model for Rex -mediated trans-activation in which Rex-viral mRNA complexes are targeted for nuclear export by the direct action of the activation domain .

These findings are consistent with a model for <protein>Rex</protein> -mediated trans-activation in which <protein>Rex-viral mRNA complexes</protein> are targeted for nuclear export by the direct action of the <protein>activation domain</protein> .


Granulocyte-macrophage colony-stimulating factor preferentially activates the 94-kD STAT5A and an 80-kD STAT5A isoform in human peripheral blood monocytes .

<protein>Granulocyte-macrophage colony-stimulating factor</protein> preferentially activates the <protein>94-kD STAT5A</protein> and an <protein>80-kD STAT5A isoform</protein> in human peripheral blood monocytes .


Granulocyte-macrophage colony-stimulating factor ( GM-CSF ) induces immediate effects in monocytes by activation of the Janus kinase ( JAK2 ) and STAT transcription factor ( STAT5 ) pathway .

<protein>Granulocyte-macrophage colony-stimulating factor</protein> ( <protein>GM-CSF</protein> ) induces immediate effects in monocytes by activation of the <protein>Janus kinase</protein> ( <protein>JAK2</protein> ) and <protein>STAT transcription factor</protein> ( <protein>STAT5</protein> ) pathway .


Recent studies have identified homologues of STAT5 , STAT5A , and STAT5B , as well as lower molecular weight variants of STAT5 .

Recent studies have identified homologues of <protein>STAT5</protein> , <protein>STAT5A</protein> , and <protein>STAT5B</protein> , as well as lower molecular weight variants of <protein>STAT5</protein> .


To define the activation of the STAT5 homologues and lower molecular weight variant in human monocytes and monocytes differentiated into macrophages by culture in macrophage-CSF ( M-CSF ) , we measured the GM-CSF induced tyrosine phosphorylation of STAT5A , STAT5B , and any lower molecular weight STAT5 isoforms .

To define the activation of the <protein>STAT5 homologues</protein> and lower molecular weight variant in <cell_type>human monocytes</cell_type> and <cell_type>monocytes</cell_type> differentiated into <cell_type>macrophages</cell_type> by culture in <protein>macrophage-CSF</protein> ( <protein>M-CSF</protein> ) , we measured the <protein>GM-CSF</protein> induced tyrosine phosphorylation of <protein>STAT5A</protein> , <protein>STAT5B</protein> , and any lower molecular weight <protein>STAT5 isoforms</protein> .


Freshly isolated monocytes expressed 94-kD STAT5A , 92-kD STAT5B , and an 80-kD STAT5A molecule .

Freshly isolated monocytes expressed <protein>94-kD STAT5A</protein> , 92-kD <protein>STAT5B</protein> , and an <protein>80-kD STAT5A molecule</protein> .


Whereas 94-kD STAT5A was clearly tyrosine phosphorylated and bound to the enhancer element , the gamma response region ( GRR ) , of the Fc gamma RI gene , substantially less tyrosine phosphorylated STAT5B bound to the immobilized GRR element .

Whereas <protein>94-kD STAT5A</protein> was clearly tyrosine phosphorylated and bound to the <dna>enhancer element</dna> , the <dna>gamma response region</dna> ( <dna>GRR</dna> ) , of the <dna>Fc gamma RI gene</dna> , substantially less tyrosine phosphorylated <protein>STAT5B</protein> bound to the immobilized <dna>GRR element</dna> .


Macrophages lost their ability to express the 80-kD STAT5A protein , but retained their ability to activate STAT5A .

Macrophages lost their ability to express the <protein>80-kD STAT5A protein</protein> , but retained their ability to activate <protein>STAT5A</protein> .


STAT5A-STAT5A homodimers and STAT5A-STAT5B heterodimers formed in response to GM-CSF .

<protein>STAT5A-STAT5A homodimers</protein> and <protein>STAT5A-STAT5B heterodimers</protein> formed in response to <protein>GM-CSF</protein> .


Therefore , activation of STAT5A predominates compared to STAT5B when assayed by direct immunoprecipitation and by evaluation of bound STATs to immobilized GRR .

Therefore , activation of <protein>STAT5A</protein> predominates compared to <protein>STAT5B</protein> when assayed by direct immunoprecipitation and by evaluation of bound <protein>STATs</protein> to immobilized <dna>GRR</dna> .


Selective activation of STAT5 homologues in addition to generation of lower molecular isoforms may provide specificity and control to genes expressed in response to cytokines such as GM-CSF .

Selective activation of <protein>STAT5 homologues</protein> in addition to generation of lower molecular isoforms may provide specificity and control to genes expressed in response to <protein>cytokines</protein> such as <protein>GM-CSF</protein> .


Translocation ( 3 ; 14 ) ( q27 ; q11 ) : a new variant translocation in a patient with non-Hodgkin 's lymphoma of B-cell type with BCL6 rearrangement .

<dna>Translocation ( 3 ; 14 ) ( q27 ; q11 )</dna> : a new variant translocation in a patient with non-Hodgkin 's lymphoma of B-cell type with <dna>BCL6</dna> rearrangement .


We report a 65-year-old woman with non-Hodgkin 's lymphoma ( NHL ) carrying a t ( 3 ; 14 ) ( q27 ; q11 ) and BCL6 rearrangement in the affected cells .

We report a 65-year-old woman with non-Hodgkin 's lymphoma ( NHL ) carrying a <dna>t ( 3 ; 14 ) ( q27 ; q11 )</dna> and <dna>BCL6</dna> rearrangement in the <cell_type>affected cells</cell_type> .


She had generalized lymphadenopathy and the bone marrow was infiltrated by lymphoma cells at presentation .

She had generalized lymphadenopathy and the bone marrow was infiltrated by <cell_type>lymphoma cells</cell_type> at presentation .


Histological diagnosis was `` malignant lymphoma , diffuse , large cell '' type according to an International Working Formulation .


Chromosome analysis revealed a t ( 3 ; 14 ) ( q27 ; q11 ) , which is a new variant translocation of t ( 3 ; 14 ) ( q27 ; q32 ) .

Chromosome analysis revealed a <dna>t ( 3 ; 14 ) ( q27 ; q11 )</dna> , which is a new variant translocation of <dna>t ( 3 ; 14 ) ( q27 ; q32 )</dna> .


Southern blot analysis showed rearrangement of BCL6 , JH , and TCR beta but not of TCR delta .

Southern blot analysis showed rearrangement of <dna>BCL6</dna> , <dna>JH</dna> , and <dna>TCR beta</dna> but not of <dna>TCR delta</dna> .


Cosmid probe of BCL6 hybridized to 14q11 and 3q27 by fluorescence in situ hybridization ( FISH ) .

<dna>Cosmid probe</dna> of <dna>BCL6</dna> hybridized to <dna>14q11</dna> and <dna>3q27</dna> by fluorescence in situ hybridization ( FISH ) .


Although the band 14q11 is a locus of T-cell receptor alpha- and delta-chains ( TCR alpha/delta ) , lymphoma cells expressed B-cell , IgGk phenotype .

Although the <dna>band 14q11</dna> is a locus of <protein>T-cell receptor alpha- and delta-chains</protein> ( <protein>TCR alpha/delta</protein> ) , <cell_type>lymphoma cells</cell_type> expressed <cell_type>B-cell , IgGk phenotype</cell_type> .


The findings suggest that a novel proto-oncogene in the vicinity of TCR alpha/delta is involved in this translocation .

The findings suggest that a <dna>novel proto-oncogene</dna> in the vicinity of <dna>TCR alpha/delta</dna> is involved in this translocation .


Transgenic expression of PML/RARalpha impairs myelopoiesis .

Transgenic expression of <protein>PML/RARalpha</protein> impairs myelopoiesis .


The translocation found in acute promyelocytic leukemia rearranges the promyelocytic leukemia gene ( PML ) on chromosome 15 with the retinoic acid receptor alpha ( RARalpha ) on chromosome 17 .

The translocation found in acute promyelocytic leukemia rearranges the <dna>promyelocytic leukemia gene</dna> ( <dna>PML</dna> ) on <dna>chromosome 15</dna> with the <dna>retinoic acid receptor alpha</dna> ( <protein>RARalpha</protein> ) on <dna>chromosome 17</dna> .


This yields a fusion transcript , PML/RARalpha , a transcription factor with reported dominant negative functions in the absence of hormone .

This yields a fusion transcript , <protein>PML/RARalpha</protein> , a <protein>transcription factor</protein> with reported dominant negative functions in the absence of hormone .


Clinical remissions induced with all-trans retinoic acid ( RA ) treatment in acute promyelocytic leukemia are linked to PML/RARalpha expression in leukemic cells .

Clinical remissions induced with all-trans retinoic acid ( RA ) treatment in acute promyelocytic leukemia are linked to <protein>PML/RARalpha</protein> expression in <cell_type>leukemic cells</cell_type> .


To evaluate the PML/RARalpha role in myelopoiesis , transgenic mice expressing PML/RARalpha were engineered .

To evaluate the <protein>PML/RARalpha</protein> role in myelopoiesis , transgenic mice expressing <protein>PML/RARalpha</protein> were engineered .


A full-length PML/RARalpha cDNA driven by the CD11b promoter was expressed in transgenic mice .

A full-length <dna>PML/RARalpha cDNA</dna> driven by the <dna>CD11b promoter</dna> was expressed in transgenic mice .


Expression was confirmed in the bone marrow with a reverse transcription PCR assay .


Basal total white blood cell and granulocyte counts did not appreciably differ between PML/RARalpha transgenic and control mice .

Basal total white blood cell and granulocyte counts did not appreciably differ between <protein>PML/RARalpha</protein> transgenic and control mice .


Cell sorter analysis of CD11b+ bone marrow cells revealed similar CD11b+ populations in transgenic and control mice .

Cell sorter analysis of <cell_type>CD11b+ bone marrow cells</cell_type> revealed similar <cell_type>CD11b+ populations</cell_type> in transgenic and control mice .


However , in vitro clonal growth assays performed on peripheral blood from transgenic versus control mice revealed a marked reduction of myeloid progenitors , especially in those responding to granulocyte/ macrophage colony-stimulating factor .

However , in vitro clonal growth assays performed on peripheral blood from transgenic versus control mice revealed a marked reduction of <cell_type>myeloid progenitors</cell_type> , especially in those responding to <protein>granulocyte/ macrophage colony-stimulating factor</protein> .


Granulocyte/macrophage colony-stimulating factor and kit ligand cotreatment did not overcome this inhibition .

<protein>Granulocyte/macrophage colony-stimulating factor</protein> and kit ligand cotreatment did not overcome this inhibition .


Impaired myelopoiesis in vivo was shown by stressing these mice with sublethal irradiation .


Following irradiation , PML/RARalpha transgenic mice , as compared with controls , more rapidly depressed peripheral white blood cell and granulocyte counts .

Following irradiation , <protein>PML/RARalpha</protein> transgenic mice , as compared with controls , more rapidly depressed peripheral white blood cell and granulocyte counts .


As expected , nearly all control mice ( 94.4 % ) survived irradiation , yet this irradiation was lethal to 45.8 % of PML/RARalpha transgenic mice .

As expected , nearly all control mice ( 94.4 % ) survived irradiation , yet this irradiation was lethal to 45.8 % of <protein>PML/RARalpha</protein> transgenic mice .


Lethality was associated with more severe leukopenia in transgenic versus control mice .


Retinoic acid treatment of irradiated PML/RARalpha mice enhanced granulocyte recovery .

Retinoic acid treatment of irradiated <protein>PML/RARalpha</protein> mice enhanced <cell_type>granulocyte</cell_type> recovery .


These data suggest that abnormal myelopoiesis due to PML/RARalpha expression is an early event in oncogenic transformation .

These data suggest that abnormal myelopoiesis due to <protein>PML/RARalpha</protein> expression is an early event in oncogenic transformation .


C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines .

<protein>C/EBP activators</protein> are required for HIV-1 replication and proviral induction in <cell_line>monocytic cell lines</cell_line> .


Previous work has shown that C/EBP sites and C/EBP transcriptional activators are necessary for HIV-1 LTR activity in monocytes/macrophages .

Previous work has shown that <dna>C/EBP sites</dna> and <protein>C/EBP transcriptional activators</protein> are necessary for <dna>HIV-1 LTR</dna> activity in <cell_type>monocytes/macrophages</cell_type> .


We have investigated the role that C/EBP proteins play in induction and replication of HIV-1 .

We have investigated the role that <protein>C/EBP proteins</protein> play in induction and replication of HIV-1 .


Ectopic expression of the dominant negative C/EBP protein LIP inhibited HIV-1 mRNA and virus production in activated U1 cells , demonstrating that C/EBP proteins are required for provirus induction .

Ectopic expression of the dominant negative <protein>C/EBP protein LIP</protein> inhibited HIV-1 mRNA and virus production in <cell_line>activated U1 cells</cell_line> , demonstrating that <protein>C/EBP proteins</protein> are required for provirus induction .


U1 lines overexpressing C/EBP activator NF-IL-6 produced more viral mRNA and virus particles following cellular activation than control lines , demonstrating that C/EBP proteins are limiting for virus transcription .

<cell_line>U1 lines</cell_line> overexpressing <protein>C/EBP activator</protein> <protein>NF-IL-6</protein> produced more <rna>viral mRNA</rna> and virus particles following cellular activation than <cell_line>control lines</cell_line> , demonstrating that <protein>C/EBP proteins</protein> are limiting for virus transcription .


HIV-1 harboring mutations within two C/EBP sites were crippled in their ability to replicate in U937 promonocytic cells , indicating that these sites are required for replication .

HIV-1 harboring mutations within two <dna>C/EBP sites</dna> were crippled in their ability to replicate in <cell_line>U937 promonocytic cells</cell_line> , indicating that these sites are required for replication .


These data identify C/EBP proteins as regulators of HIV-1 expression in monocytes/macrophages .

These data identify <protein>C/EBP proteins</protein> as regulators of HIV-1 expression in <cell_type>monocytes/macrophages</cell_type> .


Epstein-Barr virus nuclear antigen 2 and latent membrane protein independently transactivate p53 through induction of NF-kappaB activity .

<protein>Epstein-Barr virus nuclear antigen 2</protein> and <protein>latent membrane protein</protein> independently transactivate <protein>p53</protein> through induction of <protein>NF-kappaB</protein> activity .


B-cell immortalization by Epstein-Barr virus ( EBV ) is dependent on permanent control of the cellular processes which normally regulate cell division and apoptosis , functions possessed by p53 in a number of normal cell types .

<cell_type>B-cell</cell_type> immortalization by Epstein-Barr virus ( EBV ) is dependent on permanent control of the cellular processes which normally regulate cell division and apoptosis , functions possessed by <protein>p53</protein> in a number of normal cell types .


In studies initiated to evaluate relationships between EBV latent genes and p53 , p53 levels were found to increase approximately 10-fold 4 to 5 days after EBV infection of purified resting human B cells ; the induced p53 was transcriptionally active .

In studies initiated to evaluate relationships between <dna>EBV latent genes</dna> and <protein>p53</protein> , <protein>p53</protein> levels were found to increase approximately 10-fold 4 to 5 days after EBV infection of purified <cell_type>resting human B cells</cell_type> ; the induced <protein>p53</protein> was transcriptionally active .


Latent membrane protein 1 and , to a lesser extent , EBV nuclear antigen 2 mediated the increase in p53 levels via activation of the NF-kappaB transcription factor .

<protein>Latent membrane protein 1</protein> and , to a lesser extent , <protein>EBV nuclear antigen 2</protein> mediated the increase in <protein>p53</protein> levels via activation of the <protein>NF-kappaB</protein> <protein>transcription factor</protein> .


Cooperation between core binding factor and adjacent promoter elements contributes to the tissue-specific expression of interleukin-3 .

Cooperation between <protein>core binding factor</protein> and <dna>adjacent promoter elements</dna> contributes to the tissue-specific expression of <protein>interleukin-3</protein> .


Tissue-specific expression of interleukin-3 ( IL-3 ) is mediated via cis-acting elements located within 315 base pairs of the transcription start .

Tissue-specific expression of <protein>interleukin-3</protein> ( <protein>IL-3</protein> ) is mediated via <dna>cis-acting elements</dna> located within 315 base pairs of the <dna>transcription start</dna> .


This is achieved in part through the positive activities of the AP-1 and Elf-1 sites in the IL-3 promoter .

This is achieved in part through the positive activities of the <dna>AP-1 and Elf-1 sites</dna> in the <dna>IL-3 promoter</dna> .


The contribution to T cell-specific expression by other promoter sites was assessed in a transient expression assay with IL-3 promoter constructs linked to a luciferase gene , focusing initially on the core binding factor ( CBF ) site , which is footprinted in vivo upon T cell activation .

The contribution to T cell-specific expression by other <dna>promoter sites</dna> was assessed in a transient expression assay with <dna>IL-3 promoter constructs</dna> linked to a <dna>luciferase gene</dna> , focusing initially on the <dna>core binding factor ( CBF ) site</dna> , which is footprinted in vivo upon T cell activation .


Activity of the CBF site is shown to be critically dependent on the adjacent activator site Act-1 .

Activity of the <dna>CBF site</dna> is shown to be critically dependent on the <dna>adjacent activator site Act-1</dna> .


Together the Act-1 and CBF sites form a functional unit ( AC unit ) with dual activity .

Together the <dna>Act-1</dna> and <dna>CBF sites</dna> form a <dna>functional unit</dna> ( <dna>AC unit</dna> ) with dual activity .


The AC unit is demonstrated to enhance basal activity of promoters both in fibroblasts and T cells .

The <dna>AC unit</dna> is demonstrated to enhance basal activity of promoters both in <cell_type>fibroblasts</cell_type> and <cell_type>T cells</cell_type> .


This activity is further inducible in activated T cells , but not in fibroblasts .

This activity is further inducible in activated <cell_type>T cells</cell_type> , but not in <cell_type>fibroblasts</cell_type> .


In addition to the already identified NIP repressor site , evidence is presented for a second repressor region that restricts promoter activity in fibroblasts .

In addition to the already identified <dna>NIP repressor site</dna> , evidence is presented for a <dna>second repressor region</dna> that restricts promoter activity in <cell_type>fibroblasts</cell_type> .


Finally , a novel positive regulatory element has been mapped in the IL-3 promoter between nucleotide -180 and -210 that leads to increased expression in T cells .

Finally , a novel <dna>positive regulatory element</dna> has been mapped in the <dna>IL-3 promoter</dna> between nucleotide -180 and -210 that leads to increased expression in <cell_type>T cells</cell_type> .


Together these results demonstrate that T cell expression of IL-3 is not specified by the activity of a single tissue-specific element , but instead involves multiple interacting elements that provide both specific positive regulation in T cells and specific negative regulation in fibroblasts .

Together these results demonstrate that T cell expression of <protein>IL-3</protein> is not specified by the activity of a single <dna>tissue-specific element</dna> , but instead involves multiple <dna>interacting elements</dna> that provide both specific positive regulation in <cell_type>T cells</cell_type> and specific negative regulation in <cell_type>fibroblasts</cell_type> .


Modulation of the expression of the IFN-gamma receptor beta-chain controls responsiveness to IFN-gamma in human peripheral blood T cells .

Modulation of the expression of the <protein>IFN-gamma receptor beta-chain</protein> controls responsiveness to <protein>IFN-gamma</protein> in <cell_type>human peripheral blood T cells</cell_type> .


IFN-gamma has potent antiproliferative and apoptotic effects in T cells that are important in determining T cell development and polarized differentiation .

<protein>IFN-gamma</protein> has potent antiproliferative and apoptotic effects in <cell_type>T cells</cell_type> that are important in determining T cell development and polarized differentiation .


Therefore , any event that enables T cells to become less responsive to IFN- gamma may potentially alter immune responsiveness to Ag .

Therefore , any event that enables <cell_type>T cells</cell_type> to become less responsive to <protein>IFN- gamma</protein> may potentially alter immune responsiveness to <protein>Ag</protein> .


In this work , we show that human peripheral blood T cells that are stimulated through the TCR and expanded with IL-2 are unresponsive to IFN-gamma , as determined by a lack of activation of jak kinases and the transcription factor , STAT1 ( alpha ) , a signal transducer and activator of transcription .

In this work , we show that <cell_type>human peripheral blood T cells</cell_type> that are stimulated through the <protein>TCR</protein> and expanded with <protein>IL-2</protein> are unresponsive to <protein>IFN-gamma</protein> , as determined by a lack of activation of <protein>jak kinases</protein> and the <protein>transcription factor</protein> , <protein>STAT1 ( alpha )</protein> , a signal transducer and activator of transcription .


This nonresponsiveness occurs because of a lack of expression of the beta- chain ( accessory factor ) of the IFN-gamma receptor , while at the same time maintaining IFN-gamma receptor alpha-chain expression .

This nonresponsiveness occurs because of a lack of expression of the <protein>beta- chain</protein> ( accessory factor ) of the <protein>IFN-gamma receptor</protein> , while at the same time maintaining <protein>IFN-gamma receptor alpha-chain</protein> expression .


Expression of the beta-chain can be restored by secondary TCR ligation or PMA treatment .

Expression of the <protein>beta-chain</protein> can be restored by secondary <protein>TCR</protein> ligation or PMA treatment .


T cell blasts treated with PMA are now responsive to IFN-gamma .

<cell_type>T cell blasts</cell_type> treated with PMA are now responsive to <protein>IFN-gamma</protein> .


When freshly isolated , highly enriched ( > 98 % ) T cells are examined for IFN-gamma responsiveness ; these cells can respond to IFN-gamma and express beta-chain .

When freshly isolated , highly enriched ( > 98 % ) <cell_type>T cells</cell_type> are examined for <protein>IFN-gamma</protein> responsiveness ; these cells can respond to <protein>IFN-gamma</protein> and express <protein>beta-chain</protein> .


Therefore , as T cells progress from primary TCR activation through IL-2 -dependent proliferation , followed by secondary TCR stimulation , their responsiveness to IFN-gamma varies , and this may affect their ability to participate in an ongoing immune response .

Therefore , as <cell_type>T cells</cell_type> progress from primary <protein>TCR</protein> activation through <protein>IL-2</protein> -dependent proliferation , followed by secondary <protein>TCR</protein> stimulation , their responsiveness to <protein>IFN-gamma</protein> varies , and this may affect their ability to participate in an ongoing immune response .


Age-related decreases in IL-2 production by human T cells are associated with impaired activation of nuclear transcriptional factors AP-1 and NF-AT .

Age-related decreases in <protein>IL-2</protein> production by <cell_type>human T cells</cell_type> are associated with impaired activation of <protein>nuclear transcriptional factors</protein> <protein>AP-1</protein> and <protein>NF-AT</protein> .


Although transcriptional factors AP-1 and nuclear factor of activated T cells ( NF-AT ) are important for the normal induction of IL-2 , it is unknown if the age-related decline in IL-2 production by activated human T cells may be associated with aberrancies in transcriptional regulatory proteins .

Although <protein>transcriptional factors</protein> <protein>AP-1</protein> and nuclear factor of activated T cells ( <protein>NF-AT</protein> ) are important for the normal induction of <protein>IL-2</protein> , it is unknown if the age-related decline in <protein>IL-2</protein> production by activated <cell_type>human T cells</cell_type> may be associated with aberrancies in <protein>transcriptional regulatory proteins</protein> .


In the current studies , IL-2 production by T cells from elderly ( mean 78 years ) and young ( mean 37 years ) humans was measured in cultures stimulated with PHA , PHA plus PMA , crosslinked anti-CD3 mAB OKT3 plus PMA , or PMA plus ionomycin .

In the current studies , <protein>IL-2</protein> production by <cell_type>T cells</cell_type> from elderly ( mean 78 years ) and young ( mean 37 years ) humans was measured in cultures stimulated with <protein>PHA</protein> , <protein>PHA</protein> plus PMA , crosslinked anti-CD3 mAB OKT3 plus PMA , or PMA plus ionomycin .


Substantial decreases of IL-2 production were observed for cell cultures from 7 of 12 elderly individuals in response to the different stimuli , whereas the levels of IL-2 produced by stimulated T cells from other elderly individuals were equivalent to those observed for stimulated T cells of young subjects .

Substantial decreases of <protein>IL-2</protein> production were observed for cell cultures from 7 of 12 elderly individuals in response to the different stimuli , whereas the levels of <protein>IL-2</protein> produced by stimulated <cell_type>T cells</cell_type> from other elderly individuals were equivalent to those observed for stimulated T cells of young subjects .


Analyses of nuclear extracts by electrophoretic DNA mobility shift assays showed that decreased IL-2 production by stimulated T cells of elderly individuals was closely associated with impairments in the activation of both AP-1 and NF-AT .

Analyses of nuclear extracts by electrophoretic DNA mobility shift assays showed that decreased <protein>IL-2</protein> production by <cell_type>stimulated T cells</cell_type> of elderly individuals was closely associated with impairments in the activation of both <protein>AP-1</protein> and <protein>NF-AT</protein> .


By contrast , T cells from elderly subjects with normal levels of IL-2 production exhibited normal activation of AP-1 and NF-AT .

By contrast , <cell_type>T cells</cell_type> from elderly subjects with normal levels of <protein>IL-2</protein> production exhibited normal activation of <protein>AP-1</protein> and <protein>NF-AT</protein> .


In addition , the results of competition experiments analyzing the normal components of NF-AT showed that the age-related reductions in stimulus-dependent NF-AT complexes corresponded to the slow migrating complexes that were composed of c-Fos/c-Jun AP-1 .

In addition , the results of competition experiments analyzing the normal components of <protein>NF-AT</protein> showed that the age-related reductions in stimulus-dependent <protein>NF-AT complexes</protein> corresponded to the slow migrating complexes that were composed of <protein>c-Fos/c-Jun</protein> <protein>AP-1</protein> .


The resting and stimulated levels of NF kappa B were reduced in T cells from certain elderly individuals ; however , alterations of NF kappa B did not correlate with changes in IL-2 expression .

The resting and stimulated levels of <protein>NF kappa B</protein> were reduced in <cell_type>T cells</cell_type> from certain elderly individuals ; however , alterations of <protein>NF kappa B</protein> did not correlate with changes in <protein>IL-2</protein> expression .


Thus , these results show that age-related impairments in the activation of AP-1 and NF-AT are closely associated with decreased expression of IL-2 and further suggest that aberrancies in the signaling pathways important for the induction of transcriptionally active c-Fos/c-Jun AP-1 may contribute to the impaired activation of NF-AT .

Thus , these results show that age-related impairments in the activation of <protein>AP-1</protein> and <protein>NF-AT</protein> are closely associated with decreased expression of <protein>IL-2</protein> and further suggest that aberrancies in the signaling pathways important for the induction of transcriptionally active <protein>c-Fos/c-Jun</protein> <protein>AP-1</protein> may contribute to the impaired activation of <protein>NF-AT</protein> .


IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines : similarities between IL-4 and IL-13 signaling .

<protein>IL-13</protein> induces phosphorylation and activation of <protein>JAK2 Janus kinase</protein> in <cell_line>human colon carcinoma cell lines</cell_line> : similarities between <protein>IL-4</protein> and <protein>IL-13</protein> signaling .


We have recently reported that IL-13R may share a component with IL-4R . Here we report that both IL-4 and IL-13 share signaling events in human colon carcinoma cell lines ( HT-29 and WiDr ) .

We have recently reported that <protein>IL-13R</protein> may share a component with <protein>IL-4R</protein> . Here we report that both <protein>IL-4</protein> and <protein>IL-13</protein> share signaling events in <cell_line>human colon carcinoma cell lines</cell_line> ( <cell_line>HT-29</cell_line> and <cell_line>WiDr</cell_line> ) .


IL-13 caused rapid phosphorylation of the three out of four members of the known Janus family of kinases ( JAKs ) .

<protein>IL-13</protein> caused rapid phosphorylation of the three out of four members of the known <protein>Janus family of kinases</protein> ( <protein>JAKs</protein> ) .


We show that JAK2 kinase is rapidly phosphorylated and activated in response to IL-13 .

We show that <protein>JAK2 kinase</protein> is rapidly phosphorylated and activated in response to <protein>IL-13</protein> .


Within 1 min of activation , JAK2 was phosphorylated , and peaked in 10 min .

Within 1 min of activation , <protein>JAK2</protein> was phosphorylated , and peaked in 10 min .


In addition , IL-13 phosphorylated insulin response substrate-1 , IL-4R p140 , JAK1 , and Tyk2 , but not JAK3 kinase .

In addition , <protein>IL-13</protein> phosphorylated <protein>insulin response substrate-1</protein> , <protein>IL-4R p140</protein> , <protein>JAK1</protein> , and <protein>Tyk2</protein> , but not <protein>JAK3 kinase</protein> .


IL-4 also stimulated all three kinases and substrates , but unlike in immune cells , IL-4 did not involve JAK3 activation for its signaling in colon cancer cell lines .

<protein>IL-4</protein> also stimulated all three <protein>kinases</protein> and substrates , but unlike in <cell_type>immune cells</cell_type> , <protein>IL-4</protein> did not involve <protein>JAK3</protein> activation for its signaling in <cell_line>colon cancer cell lines</cell_line> .


Furthermore , JAK2 associated with the IL-4R p140 before and after stimulation with IL-13 .

Furthermore , <protein>JAK2</protein> associated with the <protein>IL-4R p140</protein> before and after stimulation with <protein>IL-13</protein> .


Both IL-13 and IL-4 induced phosphorylation of IL-4 STAT ( STAT6 ) but not STAT1 , STAT3 , or STAT5 .

Both <protein>IL-13</protein> and <protein>IL-4</protein> induced phosphorylation of <protein>IL-4 STAT</protein> ( <protein>STAT6</protein> ) but not <protein>STAT1</protein> , <protein>STAT3</protein> , or <protein>STAT5</protein> .


125I-IL-13 did not bind to colon cancer cell lines , but unlabeled IL-13 competed for the binding of 125I-IL-4 .

<protein>125I-IL-13</protein> did not bind to <cell_line>colon cancer cell lines</cell_line> , but unlabeled <protein>IL-13</protein> competed for the binding of <protein>125I-IL-4</protein> .


Our data suggest that IL-13 utilizes IL-4R and its signaling pathway , and JAK2 may play an important role in the function of IL-4R and IL-13R in colon cancer cells .

Our data suggest that <protein>IL-13</protein> utilizes <protein>IL-4R</protein> and its signaling pathway , and <protein>JAK2</protein> may play an important role in the function of <protein>IL-4R</protein> and <protein>IL-13R</protein> in <cell_type>colon cancer cells</cell_type> .


Differential regulation of IL-6 gene transcription and expression by IL-4 and IL-10 in human monocytic cell lines .

Differential regulation of <dna>IL-6 gene</dna> transcription and expression by <protein>IL-4</protein> and <protein>IL-10</protein> in <cell_line>human monocytic cell lines</cell_line> .


IL-4 and IL-10 inhibit the cytokine production and mRNA expression by monocytes/macrophages .

<protein>IL-4</protein> and <protein>IL-10</protein> inhibit the <protein>cytokine</protein> production and mRNA expression by <cell_type>monocytes/macrophages</cell_type> .


To investigate the molecular mechanism of the inhibitory effect on transcriptional or post-transcriptional regulation of IL-6 gene expression by IL-4 and IL-10 , we studied IL-6 production , expression level of IL-6 mRNA , IL-6 promoter activity , transcriptional activity of NF-kappaB and NF-IL-6 , and IL-6 mRNA stability in human monocytic cell lines , THP-1 and U937 , stimulated by PMA and LPS in the absence or the presence of IL-4 or IL-10 .

To investigate the molecular mechanism of the inhibitory effect on transcriptional or post-transcriptional regulation of <dna>IL-6 gene</dna> expression by <protein>IL-4</protein> and <protein>IL-10</protein> , we studied <protein>IL-6</protein> production , expression level of <rna>IL-6 mRNA</rna> , <protein>IL-6</protein> promoter activity , transcriptional activity of <protein>NF-kappaB</protein> and <protein>NF-IL-6</protein> , and <rna>IL-6 mRNA</rna> stability in <cell_line>human monocytic cell lines</cell_line> , <cell_line>THP-1</cell_line> and <cell_line>U937</cell_line> , stimulated by PMA and LPS in the absence or the presence of <protein>IL-4</protein> or <protein>IL-10</protein> .


Both IL-4 and IL-10 were seen to inhibit IL-6 production and the expression of IL-6 mRNA in both monocytic cell lines studied .

Both <protein>IL-4</protein> and <protein>IL-10</protein> were seen to inhibit <protein>IL-6</protein> production and the expression of <rna>IL-6 mRNA</rna> in both <cell_line>monocytic cell lines</cell_line> studied .


In chloramphenicol acetyltransferase assays , utilizing the transient transfection of a chloramphenicol acetyltransferase reporter plasmid containing the IL-6 gene promoter , IL-4 , but not IL-10 , suppressed the transcriptional activity of the IL-6 gene promoter stimulated by PMA and LPS .

In <protein>chloramphenicol acetyltransferase</protein> assays , utilizing the transient transfection of a <dna>chloramphenicol acetyltransferase reporter plasmid</dna> containing the <dna>IL-6 gene promoter</dna> , <protein>IL-4</protein> , but not <protein>IL-10</protein> , suppressed the transcriptional activity of the IL-6 gene promoter stimulated by PMA and LPS .


Electrophoretic mobility shift assays showed that IL-4 , but not IL-10 , inhibited nuclear NF-kappaB activity , and that IL-4 and IL-10 did not affect NF- IL-6 activity .

Electrophoretic mobility shift assays showed that <protein>IL-4</protein> , but not <protein>IL-10</protein> , inhibited nuclear <protein>NF-kappaB</protein> activity , and that <protein>IL-4</protein> and <protein>IL-10</protein> did not affect NF- <protein>IL-6</protein> activity .


On the other hand , IL-10 enhanced the degradation of IL-6 mRNA in a mRNA stability assay .

On the other hand , <protein>IL-10</protein> enhanced the degradation of <rna>IL-6 mRNA</rna> in a mRNA stability assay .


These results suggest that IL-4 may inhibit the transcription of the IL-6 gene by affecting NF-kappaB binding activity , while IL-10 may inhibit the IL-6 mRNA levels post-transcriptionally , without suppressing promoter activity .

These results suggest that <protein>IL-4</protein> may inhibit the transcription of the <dna>IL-6 gene</dna> by affecting <protein>NF-kappaB</protein> binding activity , while <protein>IL-10</protein> may inhibit the <rna>IL-6 mRNA</rna> levels post-transcriptionally , without suppressing promoter activity .


Therefore , we conclude that IL-4 and IL-10 inhibit IL-6 production by different mechanisms in human monocytic cell lines .

Therefore , we conclude that <protein>IL-4</protein> and <protein>IL-10</protein> inhibit <protein>IL-6</protein> production by different mechanisms in <cell_line>human monocytic cell lines</cell_line> .


Activation of nuclear factor of activated T cells in a cyclosporin A-resistant pathway .

Activation of <protein>nuclear factor of activated T cells</protein> in a cyclosporin A-resistant pathway .


The mechanism of action of the immunosuppressive drug cyclosporin A ( CsA ) is the inactivation of the Ca2+/calmodulin-dependent serine-threonine phosphatase calcineurin by the drug-immunophilin complex .

The mechanism of action of the immunosuppressive drug cyclosporin A ( CsA ) is the inactivation of the <protein>Ca2+/calmodulin-dependent serine-threonine phosphatase</protein> <protein>calcineurin</protein> by the <protein>drug-immunophilin complex</protein> .


Inactive calcineurin is unable to activate the nuclear factor of activated T cells ( NFAT ) , a transcription factor required for expression of the interleukin 2 ( IL-2 ) gene .

Inactive <protein>calcineurin</protein> is unable to activate the <protein>nuclear factor of activated T cells</protein> ( <protein>NFAT</protein> ) , a <protein>transcription factor</protein> required for expression of the <dna>interleukin 2 ( IL-2 ) gene</dna> .


IL-2 production by CsA-treated cells is therefore dramatically reduced .

<protein>IL-2</protein> production by <cell_line>CsA-treated cells</cell_line> is therefore dramatically reduced .


We demonstrate here , however , that NFAT can be activated , and significant levels of IL-2 can be produced by the CsA-resistant CD28 -signaling pathway .

We demonstrate here , however , that <protein>NFAT</protein> can be activated , and significant levels of <protein>IL-2</protein> can be produced by the CsA-resistant <protein>CD28</protein> -signaling pathway .


In transient transfection assays , both multicopy NFAT -and IL-2 promoter-beta-galactosidase reporter gene constructs could be activated by phorbol 12-myristate 13-acetate ( PMA ) /alpha- CD28 stimulation , and this activation was resistant to CsA .

In transient transfection assays , both multicopy <protein>NFAT</protein> -and <dna>IL-2 promoter-beta-galactosidase reporter gene constructs</dna> could be activated by phorbol 12-myristate 13-acetate ( PMA ) /alpha- <protein>CD28</protein> stimulation , and this activation was resistant to CsA .


Electrophoretic mobility shift assay showed the induction of a CsA-resistant NFAT complex in the nuclear extracts of peripheral blood T cells stimulated with PMA plus alphaCD28 .

Electrophoretic mobility shift assay showed the induction of a <protein>CsA-resistant NFAT complex</protein> in the nuclear extracts of <cell_type>peripheral blood T cells</cell_type> stimulated with PMA plus <protein>alphaCD28</protein> .


Peripheral blood T cells stimulated with PMA /alphaCD28 produced IL-2 in the presence of CsA .

<cell_type>Peripheral blood T cells</cell_type> stimulated with PMA <protein>/alphaCD28</protein> produced <protein>IL-2</protein> in the presence of CsA .


Collectively , these data suggest that NFAT can be activated and IL-2 can be produced in a calcineurin independent manner .

Collectively , these data suggest that <protein>NFAT</protein> can be activated and <protein>IL-2</protein> can be produced in a <protein>calcineurin</protein> independent manner .


Effects of interleukin-10 on human peripheral blood mononuclear cell responses to Cryptococcus neoformans , Candida albicans , and lipopolysaccharide .

Effects of <protein>interleukin-10</protein> on <cell_type>human peripheral blood mononuclear cell</cell_type> responses to Cryptococcus neoformans , Candida albicans , and lipopolysaccharide .


Deactivation of mononuclear phagocytes is critical to limit the inflammatory response but can be detrimental in the face of progressive infection .

Deactivation of <cell_type>mononuclear phagocytes</cell_type> is critical to limit the inflammatory response but can be detrimental in the face of progressive infection .


We compared the effects of the deactivating cytokine interleukin 10 ( IL-10 ) on human peripheral blood mononuclear cell ( PBMC ) responses to lipopolysaccharide ( LPS ) , Cryptococcus neoformans , and Candida albicans .

We compared the effects of the <protein>deactivating cytokine</protein> <protein>interleukin 10</protein> ( <protein>IL-10</protein> ) on <cell_type>human peripheral blood mononuclear cell</cell_type> ( <cell_type>PBMC</cell_type> ) responses to lipopolysaccharide ( LPS ) , Cryptococcus neoformans , and Candida albicans .


IL-10 effected dose-dependent inhibition of tumor necrosis factor alpha ( TNF-alpha ) release in PBMC stimulated by LPS and C. neoformans , with significant inhibition seen with 0.1 U/ml and greater than 90 % inhibition noted with 10 U/ml .

<protein>IL-10</protein> effected dose-dependent inhibition of <protein>tumor necrosis factor alpha</protein> ( <protein>TNF-alpha</protein> ) release in <cell_type>PBMC</cell_type> stimulated by LPS and C. neoformans , with significant inhibition seen with 0.1 U/ml and greater than 90 % inhibition noted with 10 U/ml .


In contrast , even at doses as high as 100 U/ml , IL-10 inhibited TNF-alpha release in response to C. albicans by only 50 % .

In contrast , even at doses as high as 100 U/ml , <protein>IL-10</protein> inhibited <protein>TNF-alpha</protein> release in response to C. albicans by only 50 % .


IL-10 profoundly inhibited release of IL-1beta from PBMC stimulated by all three stimuli .

<protein>IL-10</protein> profoundly inhibited release of <protein>IL-1beta</protein> from <cell_type>PBMC</cell_type> stimulated by all three stimuli .


TNF-alpha mRNA and release was inhibited even if IL-10 was added up to 8 h after cryptococcal stimulation .

<rna>TNF-alpha mRNA</rna> and release was inhibited even if <protein>IL-10</protein> was added up to 8 h after cryptococcal stimulation .


In contrast , inhibition of IL-1 beta mRNA was of lesser magnitude and occurred only when IL-10 was added within 2 h of cryptococcal stimulation .

In contrast , inhibition of <rna>IL-1 beta mRNA</rna> was of lesser magnitude and occurred only when <protein>IL-10</protein> was added within 2 h of cryptococcal stimulation .


IL-10 inhibited translocation of NF-kappaB in response to LPS but not the fungal stimuli .

<protein>IL-10</protein> inhibited translocation of <protein>NF-kappaB</protein> in response to LPS but not the fungal stimuli .


All three stimuli induced IL-10 production in PBMC , although over 10-fold less IL-10 was released in response to C. neoformans compared with LPS and C. albicans .

All three stimuli induced <protein>IL-10</protein> production in <cell_type>PBMC</cell_type> , although over 10-fold less <protein>IL-10</protein> was released in response to C. neoformans compared with LPS and C. albicans .


Thus , while IL-10 has deactivating effects on PBMC responses to all three stimuli , disparate stimulus- and response-specific patterns of deactivation are seen .

Thus , while <protein>IL-10</protein> has deactivating effects on <cell_type>PBMC</cell_type> responses to all three stimuli , disparate stimulus- and response-specific patterns of deactivation are seen .


Inhibition by IL-10 of proinflammatory cytokine release appears to occur at the level of gene transcription for TNF-alpha and both transcriptionally and posttranscriptionally for IL-1beta .

Inhibition by <protein>IL-10</protein> of <protein>proinflammatory cytokine</protein> release appears to occur at the level of gene transcription for <protein>TNF-alpha</protein> and both transcriptionally and posttranscriptionally for <protein>IL-1beta</protein> .


Characterization and purification of a protein kinase C substrate in human B cells .

Characterization and purification of a <protein>protein kinase C substrate</protein> in <cell_type>human B cells</cell_type> .


Identification as lymphocyte-specific protein 1 ( LSP1 ) .

Identification as <protein>lymphocyte-specific protein 1</protein> ( <protein>LSP1</protein> ) .


Incubation of B-chronic lymphocytic leukemia ( B-CLL ) cells with phorbol esters resulted in the phosphorylation of two major PKC substrates , MARCKS ( myristoylated , alanine-rich C kinase substrate ) and MRP ( MARCKS-related protein ) , and of a third protein , with an apparent m.w. of 60 , 000 that was the most prominent protein kinase C substrate in these cells .

Incubation of <cell_line>B-chronic lymphocytic leukemia ( B-CLL ) cells</cell_line> with phorbol esters resulted in the phosphorylation of two major <protein>PKC substrates</protein> , <protein>MARCKS</protein> ( <protein>myristoylated , alanine-rich C kinase substrate</protein> ) and <protein>MRP</protein> ( <protein>MARCKS-related protein</protein> ) , and of a third protein , with an apparent m.w. of 60 , 000 that was the most prominent <protein>protein kinase C substrate</protein> in these cells .


p60 phosphorylation was time and PMA dose dependent , and was induced by cell-permeable diacylglycerol , but not by inactive phorbol esters .

<protein>p60</protein> phosphorylation was time and PMA dose dependent , and was induced by cell-permeable diacylglycerol , but not by inactive phorbol esters .


Two-dimensional electrophoretic analysis of the protein phosphorylation pattern from the B cell line CESS demonstrated the identity between the p60 protein expressed in this cell line and that expressed in B-CLL cells .

Two-dimensional electrophoretic analysis of the protein phosphorylation pattern from the <cell_line>B cell line CESS</cell_line> demonstrated the identity between the <protein>p60 protein</protein> expressed in this cell line and that expressed in <cell_line>B-CLL cells</cell_line> .


p60 was purified from CESS cells and peptide microsequencing of this protein revealed that it was lymphocyte-specific protein 1 ( LSP1 ) , that is here characterized as the most prominent protein kinase C substrate in B cells .

<protein>p60</protein> was purified from <cell_line>CESS cells</cell_line> and peptide microsequencing of this protein revealed that it was <protein>lymphocyte-specific protein 1</protein> ( <protein>LSP1</protein> ) , that is here characterized as the most prominent <protein>protein kinase C substrate</protein> in <cell_type>B cells</cell_type> .


Transcription factors of T and B lymphocytes -- basic research and clinical perspectives for gastroenterology .

<protein>Transcription factors</protein> of <cell_type>T and B lymphocytes</cell_type> -- basic research and clinical perspectives for gastroenterology .


Tissue specific regulation of gene expression by transcription factors is a fascinating new field in molecular immunology .

Tissue specific regulation of gene expression by <protein>transcription factors</protein> is a fascinating new field in molecular immunology .


This review summarizes data on specific regulation of promoters and enhancers by nuclear trans-acting factors in lymphocytes .

This review summarizes data on specific regulation of <dna>promoters</dna> and <dna>enhancers</dna> by <protein>nuclear trans-acting factors</protein> in <cell_type>lymphocytes</cell_type> .


The structural classes of transcription factors are described and basic methods for detection and analysis of transcription factors are detailed .

The structural classes of <protein>transcription factors</protein> are described and basic methods for detection and analysis of <protein>transcription factors</protein> are detailed .


Furthermore , the most important trans-acting factors of T and B lymphocytes ( e.g . NF-kB , NF-AT and STAT families ) and their functional importance are described .

Furthermore , the most important <protein>trans-acting factors</protein> of <cell_type>T and B lymphocytes</cell_type> ( e.g . <protein>NF-kB</protein> , <protein>NF-AT</protein> and <protein>STAT families</protein> ) and their functional importance are described .


Several methods for specific down-regulation of transcription factors are shown that may be relevant to treatment of human disease .

Several methods for specific down-regulation of <protein>transcription factors</protein> are shown that may be relevant to treatment of human disease .


The data are discussed with regard to their potential clinical relevance for gastroenterology .


Selective effects of DNA damaging agents on HIV long terminal repeat activation and virus replication in vitro .

Selective effects of DNA damaging agents on <dna>HIV long terminal repeat</dna> activation and virus replication in vitro .


Much attention has recently focused on the observation that UV light can activate the long terminal repeat ( LTR ) of the human immunodeficiency virus ( HIV ) .

Much attention has recently focused on the observation that UV light can activate the <dna>long terminal repeat</dna> ( <dna>LTR</dna> ) of the human immunodeficiency virus ( HIV ) .


Although the mechanism of LTR activation remains obscure , several lines of investigation have suggested that it is a result of activation of the NF-kappa B transcription factor ( s ) following signaling events related to generalized DNA damage .

Although the mechanism of <dna>LTR</dna> activation remains obscure , several lines of investigation have suggested that it is a result of activation of the <protein>NF-kappa B</protein> <protein>transcription factor</protein> ( s ) following signaling events related to generalized DNA damage .


In this report , we present data demonstrating that HIV LTR activation is not a general consequence of cellular DNA damage , but rather a process unique to specific genotoxic stimuli , and that it does not necessarily depend on activation of NF-kappa B .

In this report , we present data demonstrating that HIV <dna>LTR</dna> activation is not a general consequence of <dna>cellular DNA</dna> damage , but rather a process unique to specific genotoxic stimuli , and that it does not necessarily depend on activation of <protein>NF-kappa B</protein> .


Furthermore , we demonstrate that several of these agents can significantly increase HIV replication and accelerate CD4 -positive lymphocyte cytotoxicity in vitro .

Furthermore , we demonstrate that several of these agents can significantly increase HIV replication and accelerate <protein>CD4</protein> -positive lymphocyte cytotoxicity in vitro .


These findings , therefore , could have clinical significance to AIDS patients with malignancies who are undergoing radiotherapy and chemotherapy .


Receptors for interleukin ( IL ) -10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements .

Receptors for <protein>interleukin ( IL ) -10 and IL-6-type cytokines</protein> use similar signaling mechanisms for inducing transcription through <dna>IL-6 response elements</dna> .


The cytoplasmic domain of the receptor for interleukin 10 ( IL-10R ) contains two box 3 sequence motifs that have been identified in the signal-transducing receptor subunits for IL-6-type cytokines and noted to be required for activating STAT3 and inducing transcription through IL-6-responsive elements .

The <protein>cytoplasmic domain</protein> of the receptor for <protein>interleukin 10</protein> ( <protein>IL-10R</protein> ) contains two <protein>box 3 sequence motifs</protein> that have been identified in the <protein>signal-transducing receptor subunits</protein> for <protein>IL-6-type cytokines</protein> and noted to be required for activating <protein>STAT3</protein> and inducing transcription through <dna>IL-6-responsive elements</dna> .


To determine whether the IL-10R has signaling functions similar to IL-6R in cells normally expressing these receptors , leukocytes of the B- , T- , and NK-cell lineages were treated with either cytokine .

To determine whether the <protein>IL-10R</protein> has signaling functions similar to <protein>IL-6R</protein> in cells normally expressing these receptors , <cell_type>leukocytes</cell_type> of the <cell_type>B- , T- , and NK-cell lineages</cell_type> were treated with either cytokine .


Both cytokines activated factors that bound to the sis-inducible element and included STAT1 and STAT3 .

Both <protein>cytokines</protein> activated factors that bound to the <dna>sis-inducible element</dna> and included <protein>STAT1</protein> and <protein>STAT3</protein> .


The cell response to IL-10 characteristically differed from that to IL-2/IL-15 , IL-4 , and interferon gamma .

The cell response to <protein>IL-10</protein> characteristically differed from that to <protein>IL-2/IL-15</protein> , <protein>IL-4</protein> , and <protein>interferon gamma</protein> .


The signaling capabilities of the IL-10R for activating specific STAT proteins and inducing gene transcription were defined by reconstitution of receptor functions in transfected tissue culture cells .

The signaling capabilities of the <protein>IL-10R</protein> for activating specific <protein>STAT proteins</protein> and inducing gene transcription were defined by reconstitution of receptor functions in <cell_line>transfected tissue culture cells</cell_line> .


COS-1 cells , co-expressing the human IL-10R and individual STAT proteins , confirmed a preference of the IL-10R for STAT3 and STAT1 .

<cell_line>COS-1 cells</cell_line> , co-expressing the human <protein>IL-10R</protein> and individual <protein>STAT proteins</protein> , confirmed a preference of the <protein>IL-10R</protein> for <protein>STAT3</protein> and <protein>STAT1</protein> .


Unlike many hematopoietin receptors , the IL-10R did not detectably activate STAT5 .

Unlike many <protein>hematopoietin receptors</protein> , the <protein>IL-10R</protein> did not detectably activate <protein>STAT5</protein> .