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)

Human immunodeficiency virus (HIV) infection may cause a dementing illness. HIV-mediated dementia is clinically and pathologically correlated with the infiltration of activated macrophages and elevated levels of tumor necrosis factor (TNF)-alpha, both of which occur in an environment of small numbers of infected cells. We examined the possibility that HIV protein Tat, which is released extracellularly from infected cells, may induce the production of TNF-alpha. Tat induced TNF-alpha mRNA and protein production dose-dependently, primarily in macrophages but also in astrocytic cells. The TNF-alpha induction was NF-kappaB-dependent and could be eliminated by inhibiting protein kinase A or protein tyrosine kinase activity. In addition, Tat-induced TNF-alpha release was also linked to phospholipase C activation. However, Tat effects were independent of protein kinase C. These observations suggest that Tat may provide an important link between HIV and macrophage/glial cell activation and suggest new therapeutic approaches for HIV dementia.
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PMID:The Tat protein of HIV-1 induces tumor necrosis factor-alpha production. Implications for HIV-1-associated neurological diseases. 927 85

The adherence of tumour cells to microvascular endothelium is believed to be a necessary step in their migration to sites of metastasis. It has been proposed that this process occurs when cell surface molecules on tumour cells bind to complementary sites on endothelial cells. The expression of these endothelial-derived cell adhesion molecules appears to be modulated by cytokines, a broad class of protein mediators which play important roles in immune and inflammatory reactions. It has been found by ourselves and others that exposure of endothelium to some cytokines augments the adhesion of inflammatory cells as well as tumour cells in in vitro assays. We used a murine model consisting of P815 mastocytoma cells and microvascular endothelium and found that pretreatment of endothelial monolayers with TNF-alpha, IL-1, LPS or PMA augmented the number of tumour cells that attach in a dose-dependent fashion. FACS analysis showed that the change in binding was due to an increase in the expression of VCAM-1 on the surface of the endothelial cell. Methylxanthines (caffeine and theophylline) as well as "classical" calcium-mobilizing agents (ionomycin and thapsigargin) inhibited the expression of VCAM-1 in MME. We also studied the possible mechanisms of TNF-alpha signal transduction in endothelial cells. We examined the involvement of protein kinases in the TNF-alpha effect. Although we found that inhibitors of PKC could inhibit the TNF-alpha effect, our studies suggest that the "classical" PKC pathway is not completely responsible for signaling since TNF-alpha did not cause translocation of PKC to the cell membrane and its effect could not be completely mimicked by PMA. We also studied the effect of TGF-beta on the binding of tumour cells to endothelium. Exposure of endothelium to TGF-beta led to the inhibition of both basal and TNF-alpha enhanced binding of P815 cells. Inhibitors of G-proteins do not abolish TGF-beta action, and PKC and PKA activators elicit an opposite effect. However, TGF-beta-mediated inhibition of both basal binding and TNF-alpha-enhanced P815 binding to endothelium is completely abolished in the presence of the protein phosphatase inhibitor okadaic acid suggesting that TGF-beta elicits its effect by stimulating protein phosphatase activity.
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PMID:Effect of cytokines on tumour cell-endothelial interactions. 934 51

The purpose of this study was to examine whether rCGRP has effects on TNF-alpha produced by mouse resident peritoneal macrophages. Macrophages were obtained from the peritoneal exudate of male Balb/c mouse. The cells were plated on culture dishes at a density of 2.5x10(5) cells per well and allowed to adhere for 2 hr. Pretreatment with rCGRP (10 nM-1 microM) for 24 hr, the macrophages were cultured with LPS 1 microg/ml for another 24 h. The medium was harvested for measuring TNF-alpha by ELISA kits. The results showed that rCGRP had no direct effects on TNF-alpha production, but it inhibited LPS-induced TNF-alpha production in a concentration-dependent manner. When rCGRP was at a concentration of 1 microM, the LPS-induced TNF-alpha production was inhibited by 39%. The effect of rCGRP was reversed by hCGRP(8-37) (10 microM), an antagonist of CGRP1 receptor. The LPS-induced TNF-alpha production from macrophages was also inhibited by forskolin 3 microM, an activator of adenylate cyclase. Furthermore, pretreatment with H-89 1 microM or Rp-cAMPS 100 microM, the inhibitors of cAMP-dependent protein kinase, the effect of rCGRP was abolished. These data suggest that the LPS-induced TNF-alpha production is inhibited by rCGRP via activation of cAMP responses in mouse resident peritoneal macrophages.
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PMID:Inhibition of LPS-induced TNF-alpha production by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages. 936 15

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

This study was undertaken to investigate the effects of propranolol, IFN-beta, and the protein kinase modulators on IFN-gamma induction of MHC class II antigen expression and cytokine production in THP-1 human monocytic cells. IFN-gamma induced expression of HLA-DR and DQ molecules and secretion of the monokines IL-1 beta and TNF-alpha in THP-1 cells in a time and dose-dependent manner. The effect of INF-gamma on class II HLA antigens was dose-dependently inhibited by IFN-beta. H-7, phloretin, staurosporine as well as GF 109203X are selective enzyme inhibitors of protein kinase C (PKC), down-regulating IFN-gamma induced MHC class II expression and cytokine production. Stimulators of PKC, like PMA, replaced IFN-gamma in the induction of monokines in THP-1 cells, whereas the addition of HA 1004 or arachidonic acid to the culture had no effect on IFN-gamma mediated changes. Blocking of phospholipase D (PLD)-derived diacylglycerol (DAG) formation by propranolol abrogated IFN-gamma increased HLA class II expression and IL-1 beta secretion, but had little effect on IFN-gamma induced TNF-alpha production. These findings appear to suggest that PLD-derived phosphatidate is not the primary source of DAG production in IFN-gamma-induced TNF-alpha secretion, but may be necessary for IFN-gamma-mediated MHC class II induction and IL-1 beta production in human monocytes, whereas phospholipase A2 may not be required for IFN-gamma activation of PKC in the process.
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PMID:Effect of propranolol and IFN-beta on the induction of MHC class II expression and cytokine production by IFN-gamma IN THP-1 human monocytic cells. 954 99

The significance of the glycosylphosphatidylinositol (GPI) anchor is unknown. Since GPI-anchored proteins mediate signaling, it has been suggested that the GPI structure serves as a signal-transducing element. However, the division of signaling functions between transmembrane and GPI-anchored proteins is unclear. Studies of distinct membrane-anchored forms of the same protein may resolve this issue. The adhesion molecule CD58 is expressed on the cell surface in both a transmembrane and a GPI-anchored form and hence provides a useful model. We studied CD58 in the human B lymphoblastoid cell line JY. In addition to mediating adhesion, CD58 is involved in signal transduction. Incubation of JY cells with immobilized anti-CD58 Abs results in extensive tyrosine phosphorylation and in secretion of TNF-alpha. We demonstrate that CD58 is associated with protein kinase(s) and with several kinase substrates. We further demonstrate that both CD58 isoforms are involved. CD58 in JY variant cells, which express only the transmembrane form, as well as CD58 in JY variant cells, which express only the GPI-anchored form, are associated with kinase activity. This association results in a phosphorylation pattern that is common to the variant and to wild-type JY cells. Thus, these findings suggest that the capacity of GPI-anchored proteins to interact with kinases is not always dependent on the GPI anchor itself.
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PMID:The glycosylphosphatidylinositol-anchored form and the transmembrane form of CD58 associate with protein kinases. 957 40

Muscle fibers are the target of T cell-mediated cytotoxic reactions in polymyositis and inclusion body myositis, while the success of myoblast transplantation depends on the absence of an immune rejection against the myofibers. In order to study the behaviour of muscle cells in an inflammatory milieu, we investigated the production of IL-6 and its modulation, including the second messenger pathways controlling it, in in vitro highly purified human myoblast cultures. We found that IL-1beta, tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) stimulated myoblast IL-6 secretion in a dose- and time-dependent manner, whereas forskolin and cholera toxin did not. HA1004 at 10 microM did not significantly affect the IL-1beta- and TNF-alpha-induced IL-6 secretion, suggesting that cAMP and protein kinase A are not sufficient to stimulate this process. To investigate the role of protein kinase C (PKC) in this signal transduction, we employed the inhibitor calphostin C, and the activators phorbol-12-myristate-13-acetate (PMA) and calcium ionophore A23187. Calphostin C blocked IL-6 secretion, PMA had a small stimulatory effect and A23187 had no effect; moreover, PKC down-regulation by PMA did not inhibit IL-1beta stimulation, while it reduced TNF-alpha stimulation. These data indicate that different PKC isoforms may be involved in TNF-alpha and IL-1beta signal transduction. Such a difference can distinguish the action of two traditionally 'overlapping' inflammatory cytokines. Our data suggest that muscle cells, like myoblasts, satellite cells and in vivo regenerating myofibers, may discriminate between different stimuli and produce IL-6 when activated in response to muscle injury.
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PMID:Myoblasts produce IL-6 in response to inflammatory stimuli. 957 14

Protein Phosphatase-1 (PP-1) appears to be the key component of the insulin signalling pathway which is responsible for bridging the initial insulin-simulated phosphorylation cascade with the ultimate dephosphorylation of insulin sensitive substrates. Dephosphorylations catalyzed by PP-1 activate glycogen synthase (GS) and simultaneously inactivate phosphorylase a and phosphorylase kinase promoting glycogen synthesis. Our in vivo studies using L6 rat skeletal muscle cells and freshly isolated adipocytes indicate that insulin stimulates PP-1 by increasing the phosphorylation status of its regulatory subunit (PP-1G). PP-1 activation is accompanied by an inactivation of Protein Phosphatase-2A (PP-2A) activity. To gain insight into the upstream kinases that mediate insulin-stimulated PP-1G phosphorylation, we employed inhibitors of the ras/MAPK, PI3-kinase, and PKC signalling pathways. These inhibitor studies suggest that PP-1G phosphorylation is mediated via a complex, cell type specific mechanism involving PI3-kinase/PKC/PKB and/or the ras/MAP kinase/Rsk kinase cascade. cAMP agonists such as SpcAMP (via PKA) and TNF-alpha (recently identified as endogenous inhibitor of insulin action via ceramide) block insulin-stimulated PP-1G phosphorylation with a parallel decrease of PP-1 activity, presumably due to the dissociation of the PP-1 catalytic subunit from the regulatory G-subunit. It appears that any agent or condition which interferes with the insulin-induced phosphorylation and activation of PP-1, will decrease the magnitude of insulin's effect on downstream metabolic processes. Therefore, regulation of the PP-1G subunit by site-specific phosphorylation plays an important role in insulin signal transduction in target cells. Mechanistic and functional studies with cell lines expressing PP-1G subunit site-specific mutations will help clarify the exact role and regulation of PP-1G site-specific phosphorylations on PP-1 catalytic function.
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PMID:Protein phosphatase-1 and insulin action. 960 13

Tuberculosis has emerged as an epidemic, extended by the large number of individuals infected with human immunodeficiency virus type 1 (HIV-1). The major goal of this study was to determine whether the mycobacterial cell wall component mannose-capped lipoarabinomannan (ManLAM) of Mycobacterium tuberculosis (M. tuberculosis) could activate transcription of HIV-1 in T cells with the use of an in vitro cell culture system. These experiments are of prime importance considering that CD4-expressing T lymphocytes represent the major virus reservoir in the peripheral blood of infected individuals. Using the 1G5 cell line harbouring the luciferase reporter gene under the control of the HIV-1 LTR, it was first found that culture protein filtrates (CFP) from M. tuberculosis or purified ManLAM could activate HIV-1 LTR-dependent gene expression unlike similarly prepared CFP extracts devoid of ManLAM. The implication of protein tyrosine kinase(s), protein kinase A and/or protein kinase C was highlighted by the abrogation of the ManLAM-mediated activation of HIV-1 LTR-driven gene expression using herbimycin A and H7. It was also determined, using electrophoresis mobility shift assays, that M. tuberculosis ManLAM led to the nuclear translocation of the transcription factor NF-kappaB. M. tuberculosis ManLAM resulted in clear induction of the luciferase gene placed under the control of the wild-type, but not the kappaB-mutated, HIV-1 LTR region. Finally, the ManLAM-mediated activation of HIV-1 LTR transcription was found to be independent of the autocrine or paracrine action of endogenous TNF-alpha. The results suggest that M. tuberculosis can upregulate HIV-1 expression in T cells and could thus have the potential to influence the pathogenesis of HIV-1 infection.
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PMID:Mycobacterium tuberculosis mannose-capped lipoarabinomannan can induce NF-kappaB-dependent activation of human immunodeficiency virus type 1 long terminal repeat in T cells. 963 75

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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