Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis of an 88-kDa gelatinolytic enzyme, identified as a zymogen of matrix metalloproteinase (proMMP)-9, was induced in the primary culture of rabbit articular chondrocytes by cotreatment with recombinant interleukin 1 beta (rIL-1 beta) and the protein kinase C (PKC) agonists, phorbol 12,13-dibutyrate (PDBu) or mezerein. Negligible 88-kDa gelatinolytic activity was produced by unstimulated cells or cells treated with a PKC activator alone at concentrations up to 100 ng/ml, and only a modest induction occurred with rIL-1 beta alone at concentrations of 1-100 ng/ml. However, when these cells were treated with a PKC activator in the presence of IL-1 beta (1 ng/ml), induction was striking, with enzymic activity detectable at a concentration as low as 1 ng/ml of mezerein or 10 ng/ml of PDBu. Rabbit chondrocytes in culture constitutively produced the zymogen of MMP-2 (proMMP-2) and its production was not altered by treatment with IL-1 beta or PKC agonists alone or in combination. Recombinant tumor necrosis factor alpha (rTNF alpha) did not substitute for IL-1 beta in inducing proMMP-9 in the presence of PKC activators, nor was the combination of IL-1 beta or TNF alpha alone effective. These data indicate that rabbit articular chondrocytes have a potential to synthesize and secrete proMMP-9 under certain biological and pathological conditions but that the expression of proMMP-9 is differently regulated from that of other MMPs.
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PMID:Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) is induced in rabbit articular chondrocytes by cotreatment with interleukin 1 beta and a protein kinase C activator. 132 11

Although several cytokines have been demonstrated to exert pleiotropic responses, there is little information on cytokine regulation of renal tubular epithelial cell function. In the present studies, we find that both T cell-derived (tumor necrosis factor-beta and interleukins 2 and 3) and monocyte/macrophage derived (tumor necrosis factor alpha and interleukin 1 beta) cytokines promote basal, arginine vasopressin- and forskolin-stimulated adenylate cyclase activity in cultured LLC-PK1 cells. No effect of TNF, IL-1 beta, and IL-2 to stimulate protein kinase C activity was observed. TNF-beta, IL-1 beta and IL-2 also modestly stimulated 3H release from 3H-arachidonic acid labeled cells. Mepacrine, a phospholipase A inhibitor, prevented TNF-beta stimulation of 3H release from 3H-arachidonic acid labeled cells and TNF-beta potentiation of adenylate cyclase activity. TNF-beta potentiation of adenylate cyclase activity and stimulation of 3H release from 3H arachidonic acid labeled cells was not prevented by pertussis toxin. These results demonstrate that several cytokines can stimulate adenylate cyclase activity while not affecting protein kinase C activity in cultured renal tubular epithelial cells. The effect of TNF-beta to stimulate adenylate cyclase appears to occur independent of pertussis toxin-sensitive substrate and may involve activation of phospholipase A.
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PMID:Cytokine regulation of adenylate cyclase activity in LLC-PK1 cells. 140 34

During infection, inflammation, immune responses, and neoplastic growth, various cytokines are produced affecting both susceptibility to and protection from cellular death. We have studied the protective effect of pretreatment of the L929 fibroblast cell line with interleukin 1 beta (IL-1 beta), IL-6, tumor necrosis factor alpha (TNF-alpha), or transforming growth factor beta 1 (TGF-beta) on subsequent TNF/actinomycin D-induced cytotoxicity. The protective effects of these cytokines on TNF cytotoxicity were time and concentration dependent. TGF-beta was the most effective cytokine, followed by TNF, IL-1 beta, and IL-6. Activators of protein kinase C also afforded protection, and TGF-beta acted synergistically with either phorbol 12-myristate 13-acetate or the calcium ionophore A-23187. TGF-beta-induced protection against TNF was observed in cells subjected to prolonged treatment with phorbol 12-myristate 13-acetate. Cells pretreated with prostaglandin E2 or cholera toxin amplified the sensitivity to TNF and inhibited TGF-beta-mediated resistance, whereas indomethacin enhanced the protective effect of TGF-beta. Cells cultured in the presence of IL-1 beta, IL-6, TNF-alpha, or TGF-beta for 6 h inhibited DNA synthesis, and this was associated with concomitant growth arrest in the G1 phase of the cell cycle. On the other hand, prostaglandin E2 or cholera toxin stimulated the progression of cells from G1 toward G2 + M which was associated with increased TNF sensitivity. We conclude that these cytokines protect against death by arresting growth in the G1 phase of the cell cycle.
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PMID:Interleukin 1, interleukin 6, tumor necrosis factor, and transforming growth factor beta increase cell resistance to tumor necrosis factor cytotoxicity by growth arrest in the G1 phase of the cell cycle. 201 1

Phorbol esters induce the differentiation of the human promonocytic cell line U937 to a monocyte/macrophage. This process is associated with the induction of interleukin 1 beta (IL-1 beta) gene expression (Strulovici, B., Daniel-Issakani, S., Oto, E., Nestor, J., Jr., Chan, H., and Ping-Tsou, A. (1989) Biochemistry 28, 3569-3576). Here we describe the induction by phorbol esters of lipopolysaccharide (LPS) responsiveness in U937 cells. Preincubation with phorbol myristate acetate (TPA, 5 x 10(-8) M) for at least 4-6 h and up to 12 h followed by 3 h of LPS treatment induced a 4-fold enhancement in the accumulation of IL-1 beta transcripts compared to treatment with TPA alone. This "priming" effect was specific for protein kinase C agonists and required de novo protein synthesis. Exposure of [35S]methionine-labeled U937 cells to phorbol esters induced the de novo synthesis of a protein which migrated with a 40-kDa molecular mass in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, had an isoelectric point of 5.7 (p 40/5.7), and was recognized by a specific antibody to the pertussis toxin (PT)-sensitive Gi2. The time course for the appearance of Gi2 correlated with that for the induction of LPS responsiveness by TPA. Moreover, the LPS response was PT-sensitive. In cells treated with LPS for 5 min, Gi2 showed diminished ADP-ribosylation by PT. Treatment of U937 cells with LPS for 30 min induced phosphorylation of Gi2 and enhanced PT labeling. In a cell-free assay, phosphorylation of Gi2 by protein kinase C type III, rendered it a better PT substrate. The present findings thus suggest: 1) that TPA induces LPS responsiveness in U937 cells via de novo synthesis of Gi2; 2) that the LPS response (enhanced IL-1 production) is linked to a pertussis toxin-sensitive G protein which we identified as Gi2; and 3) that LPS leads to phosphorylation of Gi2.
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PMID:Lipopolysaccharide response is linked to the GTP binding protein, Gi2, in the promonocytic cell line U937. 251 Dec

Isolated islets from adult rats or obese hyperglycemic (ob/ob) mice were incubated with human recombinant interleukin 1 beta in order to study whether the acute effects of the cytokine on islet insulin release are associated with changes in islet phospholipase C activity, Ca2+ handling or protein phosphorylation. The cytokine stimulated insulin release both at low and high glucose concentrations during one hour incubations. In short-term incubations (less than 1 min) interleukin 1 beta did not affect the production of inositoltrisphosphate. Addition of interleukin 1 beta affected neither the cytoplasmic free Ca2+ concentration at rest nor that observed subsequent to stimulation with a high concentration of glucose. Furthermore, the endogenous protein kinase C activity, as visualized by immunoprecipitation of a 32P-labelled substrate for this enzyme, was not altered by interleukin 1 beta. Separation of 32P-labelled proteins by means of 2-dimensional gel electrophoresis failed to reveal any specific effects of the cytokine on the total protein phosphorylation activity. These results suggest that the stimulatory effects on insulin release exerted by interleukin 1 beta are not caused by acute activation of phospholipase C and protein kinase C or by an alteration of islet Ca2+ handling of the B-cells.
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PMID:Human interleukin 1 beta stimulates islet insulin release by a mechanism not dependent on changes in phospholipase C and protein kinase C activities or Ca2+ handling. 268 30

Treatment of human promyelocytic leukemia cells U937 with phorbol 12-myristate 13-acetate (TPA) induces them to differentiate into monocytic cells [Harris, P., & Ralph, P. (1985) J. Leukocyte Biol. 37, 407-422]. Here we investigated the effects of TPA on interleukin 1 gene expression and the possible role of protein kinase C (PKC) in this process. Addition of TPA to serum-starved U937 cells induced the expression of the interleukin 1 beta (IL-1 beta) gene. This effect was apparent as early as 2 h and peaked at 24 h in the presence of 5 X 10(-8) M TPA. Higher concentrations of TPA, which partially or totally depleted protein kinase C levels in the cells (10(-9)-2 X 10(-5) M), had an inhibitory effect on IL-1 beta mRNA expression. Cell-permeable 1,2-dioctanoyl-sn-glycerol (diC8), a diacylglycerol that activates PKC in intact cells and cell-free systems, did not mimic the effect of TPA on the IL-1 beta mRNA induction. To determine the protein kinase C isozymes present in the control and TPA- (5 X 10(-8) M) treated U937 cells, we prepared antipeptide antibodies that specifically recognize the alpha, beta, and gamma isoforms of protein kinase C in rat brain cytosol and U937 cell extracts. In "control" U937 cells, 30% of PKC alpha was particulate, and PKC beta was cytosolic, while there was no detectable PKC gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of distinct protein kinase C isozymes by phorbol esters: correlation with induction of interleukin 1 beta gene expression. 278 67

In the absence of monocytes, resting T lymphocytes extensively purified from human peripheral blood failed to proliferate when stimulated with a mixture of calcium ionophore, which elevates intracellular calcium levels, and TPA, which activated protein kinase C. A third signal, i.e., the triggering via CD3 or CD2 molecules, was necessary in order to observe proliferation. These highly purified T cells required the presence of monocytes in both CD3 and CD2 systems for their proliferation. Exogenous interleukin 1 clearly substituted for monocytes in CD2- but not in CD3- triggered T-cell proliferation. In contrast, the effect of CD2 and CD3 antibodies on Ca++ influx was apparently not dependent on the presence of monocytes. In the presence or absence of the monocytes, CD3, as well as certain combinations of CD2 monoclonal antibodies including the D66 monoclonal antibody, were able to increase the intracellular calcium concentration as measured by Quin 2 fluorescence. EGTA, a Ca++ chelator, completely inhibited CD2- and CD3- mediated T-cell proliferation, indicating that calcium uptake is necessary during the T-cell proliferation. The addition of TPA abrogated the inhibitory effect of EGTA and completely restored the response of the T cells stimulated by CD3, but not by CD2, monoclonal antibodies. In the CD2 pathway, EGTA-inhibited proliferation of T cells could be completely restored by addition of exogenous interleukin 2 as well as exogenous recombinant interleukin 1. Our results indicate that EGTA inhibits the production of interleukin 1 but has no direct effect on either interleukin 2 production or on Tac antigen expression. In this system, recombinant interleukin 1 alpha demonstrated a more potent ability for restoring the T-cell response than did recombinant interleukin 1 beta. These results suggest that interleukin 1 could act as a potent costimulatory factor in the non-antigen-specific T-cell activation.
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PMID:Comparison of signals delivered through CD3 and CD2 for T-cell activation: the role of calcium influx and interleukin 1. 314 81

Tumour necrosis factor (TNF) and related cytokines have been found to alter the phenotype of vascular endothelial cells so as to promote coagulation, inflammation and immunity. We have used recombinant human TNF, lymphotoxin (LT), interleukin 1 alpha (IL-1 alpha) and interleukin 1 beta (IL-1 beta) to study and compare the effects of these molecules on cultured human endothelial cells (HEC). All four mediators cause HEC monolayers to reorganize from an epithelioid to a fibroblastoid morphology. Reorganization is slow (days), reversible upon cytokine withdrawal and enhanced by co-addition of immune interferon. Coincident with morphological change, TNF and LT (but not IL-1 alpha or IL-1 beta) cause a marked increase in HLA-A, B mRNA and antigen expression. TNF and LT also induce a slow increase in the mRNA levels and cell-surface expression of IL-1 species. All four cytokines have been reported to enhance HEC adhesiveness for lymphocytes and inflammatory leucocytes; these changes temporally coincide with a rapid (hours) and sustained increase in expression of intercellular adhesion molecule 1 (ICAM-1), and with a rapid but transient de novo expression of an endothelial-leucocyte adhesion molecule (detected by antibody H4/18), respectively. TNF and LT induce reciprocal tachyphylaxis for the reinduction of H4/18 binding but do not inhibit induction by IL-1 alpha and IL-1 beta; similarly, IL-1 alpha and IL-1 beta induce reciprocal tachyphylaxis but do not inhibit TNF or LT. We have used the binding of H4/18 to explore the mechanism of action of TNF. Tumour-promoting phorbol esters, but not agents which increase cytoplasmic calcium concentrations, were found to induce binding, suggesting a possible involvement of the protein kinase C pathway in the response of HEC to TNF. Cells pretreated for 24 hours with phorbol esters cannot be reinduced to express H4/18 binding by phorbol esters yet retain full responsiveness to TNF. Thus TNF also appears to act on HEC through a pathway independent of protein kinase C activation. Collectively, these effects of TNF and related cytokines may be understood as examples of endothelial cell activation.
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PMID:Effects of tumour necrosis factor and related cytokines on vascular endothelial cells. 333 9

In cultured vascular smooth muscle cells (VSMC), inflammatory cytokines such as interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha stimulated nitric oxide (NO) production via the expression of an inducible type of NO synthase (iNOS). A potent vasoconstrictor, angiotensin II (Ang II), which causes a rapid phospholipase C-mediated phosphoinositide hydrolysis via the Ang II type 1 (AT1) receptor in VSMC, by itself did not stimulate the production of nitrite, a stable metabolite of NO, but dose dependently inhibited the IL-1 beta-induced nitrite production. This inhibitory effect of Ang II was blocked by an AT1 receptor antagonist, CV-11974, but not by an Ang II type 2 receptor antagonist, PD 123319. The presence of Ang II during the early induction phase of iNOS was required for this inhibition. Consistently, Ang II suppressed IL-1 beta-induced increases in iNOS mRNA and protein levels. Ang II also inhibited increases in nitrite production and iNOS mRNA and protein levels caused by tumor necrosis factor alpha. A protein kinase C-activating phorbol ester, phorbol 12-myristate 13-acetate, and a membrane-permeable diacylglycerol, 1,2-dioctanoyl-glycerol, similarly inhibited the IL-1 beta-induced nitrite production and iNOS mRNA and protein expression, although repetitive additions were needed in the case of diacylglycerol. These results indicate that Ang II negatively modulates cytokine-induced NO production by blocking iNOS expression via the AT1 receptor in VSMC and suggest that protein kinase C could be involved in this process.
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PMID:Angiotensin II inhibits cytokine-stimulated inducible nitric oxide synthase expression in vascular smooth muscle cells. 751 70

In cultured glomerular mesangial cells, interleukin 1 beta (IL-1 beta) has been shown to induce a dose- and time-dependent accumulation of nitrite, a stable metabolite of nitric oxide (NO). In parallel, increased levels of mRNA of an inducible macrophage-type of nitric oxide synthase (iNOS) were observed after incubating mesangial cells with IL-1 beta. Here we report that addition of the biologically active phorbol esters, phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDBu), dose-dependently inhibited the IL-1 beta-stimulated increase in iNOS mRNA levels and nitrite production. In contrast, the biologically inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate, had no effect on cytokine induction of iNOS and nitrite formation. Incubation of mesangial cells with PMA or PDBu alone, in the absence of IL-1 beta, did not trigger any iNOS expression. Time-course studies indicated that phorbol ester needs to be added for only 1 h in order to maximally inhibit cytokine-induced nitrite production. Down-regulation of protein kinase C (PKC)-alpha and -delta isoenzymes by 8 h PMA or PDBu treatment before stimulation with IL-1 beta still resulted in full inhibition of iNOS induction. In contrast, a 24 h treatment of mesangial cells with PMA or PDBu, a regimen that also causes depletion of PKC-epsilon, abolished inhibition of IL-1 beta-induced iNOS expression and nitrite production. In addition, the selective PKC inhibitor calphostin C potentiated IL-1 beta induction of iNOS activity. In summary these data suggest that IL-1 beta induction of iNOS expression is tonically suppressed by PKC and the epsilon-isoenzyme is the most likely candidate mediating this effect.
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PMID:Possible role of protein kinase C-epsilon isoenzyme in inhibition of interleukin 1 beta induction of nitric oxide synthase in rat renal mesangial cells. 752 44


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