Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV-1 Nef protein shares a significant homology with the immunosuppressive and highly conserved retroviral transmembrane protein p15E. In the present study, extracellular Nef protein is shown to induce interleukin (IL)-10 mRNA expression in human peripheral blood mononuclear cells as well as in cells of H9 T and U937 promonocytic human cell lines. Release of IL-10 protein into supernatants of peripheral blood mononuclear cells stimulated with Nef is dose-dependent. Expression of cytokines IL-2, IL-4, IL-5, IL-12 p40, IL-13, and interferon gamma is not affected by Nef stimulation. IL-10 protein production induced by Nef is inhibited by the calcium/calmodulin phosphodiesterase inhibitor W-7 but not by the protein kinase A inhibitor H-89 nor the protein kinase C inhibitors staurosporine and calphostin C. The calcium chelating agent EGTA also inhibits the IL-10 production induced by Nef, and this inhibition is reversed by the addition of calcium along with Nef. These findings indicate that extracellular Nef may contribute to the immunopathogenesis of HIV infection by inducing IL-10.
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PMID:Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium/calmodulin-dependent phosphodiesterase signal transduction pathway. 909 66

IL-4 activates resting B cells and, in conjunction with cosignals such as anti-IgM (anti-mu) Ab or CD40 ligand, modulates progression of B cells through the cell cycle, leading to proliferation. In this study, we show that the mitogenic combination of IL-4 and anti-mu Ab triggered induction of cyclin D3 and up-regulated cyclin-dependent kinase (cdk) 6 expression, whereas such regulation was not observed in B cells activated by IL-4 or anti-mu Ab alone. Furthermore, cyclin D3 immunoprecipitated fron as associated with cdk6, and the cyclin D3/cdk6 complex was able to phosphorylate recombinant retinoblastoma protein in vitro. In addition, B cells activated with either IL-4 or 1L-13 alone expressed a higher amount of p27kip1 (p27) cdk inhibitor than nonstimulated cells. In contrast, p27 expression was decreased when cells were activated with mitogenic combinations of IL-4 and anti-mu Ab or anti-CD40 mAb. We also observed that the IL-4-mediated inhibition of the proliferation of anti-mu/IL-2- or anti-mu/phorbol 12,13-dibutyrate-activated human leukemic B cells was associated with the maintenance of large amounts of p27 in these cells. These data suggest that IL-4 controls B cell proliferation by action during at least two steps of the regulation of the cell cycle, cyclin D3/cdk6 complex regulation and p27 inhibitor expression.
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PMID:Modulation of the p27kip1 cyclin-dependent kinase inhibitor expression during IL-4-mediated human B cell activation. 912 Feb 57

Mast cell activation-secretion by several signal transduction pathways results in the release of proinflammatory mediators including histamine, proteases, arachidonic acid metabolites and multifunctional cytokines. In the present investigations the activation-secretion responses of the cytokine-independent, cloned 10P2 cell line have been explored. [14C]Serotonin (5-HT) preloaded cells were stimulated with antigen, with and without IL-4, ionophore A23187, thapsigargin or phorbol myristate acetate (PMA). Following passive sensitization with anti-dinitrophenol (anti-DNP) IgE, mast cells released up to 31% of incorporated [14C]5-HT when stimulated with specific antigen (DNP-human serum albumin). This response was potentiated by pretreatment with IL-4. Significant degranulation (50%) was noted following treatment with calcium ionophore A23187, thapsigargin and ionophore A23187/PMA. Collectively, these results suggest that 10P2 cells undergo activation-secretion responses, assessed as degranulation of preloaded [14C]5-HT when challenged with IgE antigen, by influx of extracellular calcium or release of intracellular calcium stores, or by direct activation of protein kinase isozymes. As a growth factor-independent cell line, 10P2 cells may be a valuable adjunct to existing mast cell model systems currently used for pharmacologic investigations.
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PMID:Activation-secretion coupling in 10P2 murine mast cells challenged with IgE-antigen, ionophore A23187, thapsigargin and phorbol ester. 912 38

Raf kinase is an important intracellular mediator in T cell signalling and may be crucial for the proliferation of this inflammatory cell. In order to elucidate its effect on cytokine production by human T cells in response to T cell receptor activation, experiments were carried out on human T cell clones using antisense (AS) oligodeoxynucleotides (ODN) to inhibit the expression of Raf kinase. AS ODN to Raf were shown to have a significant effect on a human Th1-like T cell clone, inhibiting antiCD3-induced IFN-gamma secretion by 76%, whereas no inhibitory effect was observed on IL-5 or IL-4 production by a Th2-like clone. IL-2 secretion from both clones was also not affected by the Raf AS ODN. In all cases, a reduction in Raf kinase within the cell was demonstrated by Western blot. Our results clearly demonstrate the importance of Raf kinase in the production of IFN-gamma from Th1 cells, but also show the lack of effect of this intracellular mediator on cytokine (IL-5, IL-4) release from Th2 cells.
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PMID:IFN-gamma production from human Th1 cells is controlled by Raf kinase. 913 May 47

The aim of the present study was to analyze the pathways regulating the expression of CD21 and CD23 B-cell differentiation antigens on human malignant B cells. Exposure of Farage cells, derived from a human B-cell lymphoma, to phorbol 12-myristate 13-acetate (PMA) down-regulated CD21 and CD23 expression, while interleukin 4 (IL4) inhibited the expression of CD21 but augmented CD23 expression. When Farage cells were stained with either anti-CD21 or anti-CD23 monoclonal antibodies (mAb), subsequent exposure to IL4 failed to change the staining of the cells, indicating that IL4 did not affect the turnover of CD21 and CD23 molecules. Inhibition of protein synthesis with cycloheximide (CXM) had no effect on the expression of CD21 molecules, but abrogated their down-regulation by IL4, suggesting that IL4 induced the synthesis of proteins which modify the processing of CD21 molecules. The inhibitory effect of IL4 on the expression of CD21 and its augmentary effect on the expression of CD23 was abrogated by H7 (1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine), an inhibitor of serine protein kinase. Staurosporine, an additional inhibitor of serine kinases also abrogated the effect of IL4 on CD23 expression. H8 (N-(2-[Methylamino]ethyl)-5-isoquinolinesulfonamide), a preferential inhibitor of protein kinases A and G, and genistein, an inhibitor of tyrosine kinases had no effect on IL4-induced modulation of CD21 and CD23 in Farage cells. The exposure of B-chronic lymphocytic leukemia (CLL) cells to PMA reduced the expression of CD21, but increased the expression of CD23. IL4 had no effect on the expression of CD21 on CLL-cells but strongly enhanced the level of CD23. H7, H8 and genistein each abrogated to a different extent the effect of IL4 on the expression of CD23 by CLL-cells. These data indicate that activation of serine/threonine kinases in malignant B cells inhibited the production of CD21 proteins, while different protein kinases appeared to be involved in up- and down-regulation of CD23 in different B lymphocytes.
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PMID:Pathways controlling the expression of surface CD21 (CR2) and CD23 (Fc(epsilon)IIR) proteins in human malignant B cells. 925 Aug 23

Expression of cytokines by T lymphocytes is a highly balanced process, involving stimulatory and inhibitory intracellular signalling pathways. In the present work, we attempted to clarify the role of cAMP on interferon-gamma (IFN-gamma), interleukin (IL)-10, IL-4 and IL-13 expression as well as on the inducible nitric oxide synthase (iNOS) expression. Treatment of phytohaemagglutinin (PHA)/phorbol 12-myristate 13-acetate (PMA)-activated Jurkat cells with either dibutyryl-cyclic adenosine monophosphate (cAMP) or pentoxifylline induced a strong inhibition of IFN-gamma mRNA expression as measured by reverse transcription (RT)-polymerase chain reaction (PCR), without affecting IL-10 expression. Both cholera toxin and prostaglandin E2 (PGE2) induced a strong inhibition of IFN-gamma mRNA expression, whereas IL-10 mRNA expression was significantly enhanced. This differential regulation of IFN-gamma and IL-10 expression was related to intracellular cAMP concentration. IL-13 and IL-4 mRNA expressions were not inhibited. We developed a new method based on immunofluorescence for intracellular cytokine detection followed by optical and computerized image processing, and our results showed that IFN-gamma protein was strongly inhibited when cells were treated with PGE2 or dibutyryl (db)-cAMP, whereas IL-10 protein was enhanced. This suggests that cAMP exerts its action at both the transcriptional and protein levels. iNOS mRNA expression was markedly elevated in the presence of PGE2. The generation of nitric oxide using sodium nitroprusside (SNP) induced a dramatic decrease of IFN-gamma, while IL-10 was enhanced; and conversely the inhibition of iNOS activity using 1-NG-monomethyl arginine (1-NMMA) induced a clear inhibition of IL-10 and IL-4, while IFN-gamma was enhanced. These results provide evidence that the protein kinase A (PKA) activation pathway plays a prominent role in the balance between the type 1 and type 2 cytokine profile in PHA/PMA-activated Jurkat cells. Data also suggest that iNOS expression is under the control of PKA activation, and that NO seems to be able to assume the polarization of activated T cells to the type 2 profile.
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PMID:Differential regulation of IFN-gamma, IL-10 and inducible nitric oxide synthase in human T cells by cyclic AMP-dependent signal transduction pathway. 930 24

We investigated the regulatory influence of several cytokines on the expression of preproenkephalin (PPE) mRNA in human peripheral blood mononuclear cells (PBMC). By use of a quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR), we demonstrate that the T helper 2 cytokines IL-4 and IL-10 are more potent in upregulating PPE mRNA expression in human PBMC than the T helper 1 cytokines IL-2 and gamma-IFN. In addition, TGF-beta is also an effective inducer of PPE mRNA. TGF-beta, IL-4 and IL-10 increase the cytoplasmatic concentration of met-enkephalin in PBMC. Secretion of met-enkephalin in the culture supernatant of IL-4- or IL-10-stimulated PBMC could not be observed, but proenkephalin A-derived met-enkephalin containing peptides could be demonstrated. IL-4 and IL-10 do not induce PPE mRNA via the same pathways. We could observe that PKA is involved in IL-4 mediated PPE mRNA induction, whereas IL-10 apparently uses another route.
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PMID:T helper 2 cytokines induce preproenkephalin mRNA expression and proenkephalin A in human peripheral blood mononuclear cells. 935 52

IL-17 is a newly described, T cell-derived cytokine with ill-defined physiologic properties. As such, we examined the release of proinflammatory mediators by human macrophages in response to recombinant human (rh) IL-17. IL-1beta and TNF-alpha expression and synthesis were up-regulated by rhIL-17 in a dose (ED50 was 50 +/- 9 ng/ml)- and time-dependent fashion, with cytokine accumulation reaching a zenith after 9 h. Release of IL-6, PGE2, IL-10, IL-12, IL-1R antagonist, and stromelysin was also stimulated by rhIL-17. IL-1beta and TNF-alpha mRNA expression levels were controlled by rhIL-17 in a complex manner with an initial 30-min inhibitory phase, and then up-regulation beginning at 1 h and reaching a plateau at about 3 h. The latter expression pattern closely mirrored the nuclear accumulation of the transcription factor nuclear factor-kappaB. cAMP mimetics isobutyl-1-methylxanthine (IBMX), forskolin, PGE2, and cholera toxin reversed rhIL-17-induced release of TNF-alpha, but had no consistent effect on induced IL-1beta synthesis. Induced release of TNF-alpha was also inhibited by serine/threonine protein kinase inhibitors KT-5720 (protein kinase A) and Calphostin C (protein kinase C), mitogen-activated protein kinase kinase inhibitor PD098059, and a nonspecific tyrosine kinase inhibitor, genistein. Calphostin C alone abrogated the rhIL-17-induced release of IL-1beta. The antiinflammatory cytokines IL-4 (p < 0.01) and IL-10 (p < 0.02) completely reversed rhIL-17-stimulated IL-1beta release, while IL-13 and TGF-beta2 were partially effective (59 and 43% diminution, respectively). IL-10 exerted a significant suppressive effect on IL-17-induced TNF-alpha release (99%, p < 0.02), while the inhibitory effects of IL-4, IL-13, and TGF-beta2 on TNF-alpha secretion were partial (48, 10, and 23%, respectively). The data suggest a pivotal role for IL-17 in initiating and/or sustaining an inflammatory response.
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PMID:IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. 953 13

The phosphatidylinositol 3-kinase (PI3K)-signaling pathway has emerged as an important component of cytokine-mediated survival of hemopoietic cells. Recently, the protein kinase PKB/akt (referred to here as PKB) has been identified as a downstream target of PI3K necessary for survival. PKB has also been implicated in the phosphorylation of Bad, potentially linking the survival effects of cytokines with the Bcl-2 family. We have shown that granulocyte/macrophage colony-stimulating factor (GM-CSF) maintains survival in the absence of PI3K activity, and we now show that when PKB activation is also completely blocked, GM-CSF is still able to stimulate phosphorylation of Bad. Interleukin 3 (IL-3), on the other hand, requires PI3K for survival, and blocking PI3K partially inhibited Bad phosphorylation. IL-4, unique among the cytokines in that it lacks the ability to activate the p21ras-mitogen-activated protein kinase (MAPK) cascade, was found to activate PKB and promote cell survival, but it did not stimulate Bad phosphorylation. Finally, although our data suggest that the MAPK pathway is not required for inhibition of apoptosis, we provide evidence that phosphorylation of Bad may be occurring via a MAPK/ERK kinase (MEK)-dependent pathway. Together, these results demonstrate that although PI3K may contribute to phosphorylation of Bad in some instances, there is at least one other PI3K-independent pathway involved, possibly via activation of MEK. Our data also suggest that although phosphorylation of Bad may be one means by which cytokines can inhibit apoptosis, it may be neither sufficient nor necessary for the survival effect.
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PMID:Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation. 963 68

To explore the role of sympathetic nervous system activation in HIV pathogenesis, we examined the effect of the neuroeffector molecule norepinephrine (NE) on HIV-1 replication in quiescently infected PBMCs that were subsequently activated with Abs to CD3 and CD28. NE accelerated HIV-1 replication at concentrations ranging from 10(-8) to 10(-5) M. This effect could be mimicked by protein kinase A (PKA) activators (forskolin or dibutyryl-cAMP) and abrogated by beta-adrenoreceptor antagonists or the PKA inhibitor rp-cAMP, indicating transduction via the adrenoreceptor signaling pathway. NE reduced cellular activation and altered the production of several HIV-modulating cytokines: IL-10 and IFN-gamma were markedly suppressed; TNF-alpha, IL-1beta, IL-2, IL-4, and IL-6 were mildly suppressed; and levels of IL-12 were not significantly altered. The addition of either exogenous IFN-gamma or IL-10 abrogated the effect of NE on virus production. Thus PKA-dependent suppression of cytokine production appears to mediate the enhancement of HIV-1 replication by NE.
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PMID:Norepinephrine accelerates HIV replication via protein kinase A-dependent effects on cytokine production. 967 Sep 34


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