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)

Primary rat astrocytes express TNF-alpha protein in response to various stimuli including a combined treatment with IFN-gamma and LPS, or IFN-gamma and IL-1 beta. This study was undertaken to further elucidate the mechanisms underlying TNF-alpha gene expression in the astrocyte, and to determine the intracellular signaling pathways involved in IFN-gamma/LPS and/or IFN-gamma/IL-1 beta induction of the TNF-alpha gene. We demonstrate that TNF-alpha mRNA is rapidly induced, and mRNA levels peak after 2 h of stimulation. De novo protein synthesis is not required for TNF-alpha expression because the inclusion of cycloheximide does not prevent expression of the gene and acts to superinduce TNF-alpha mRNA levels. IFN-gamma/LPS induces transcriptional activation of the TNF-alpha gene as assessed by nuclear run-on experiments. Cycloheximide acts to increase both transcription of the TNF-alpha gene and stability of TNF-alpha mRNA thereby resulting in increased TNF-alpha steady state mRNA levels. Two protein kinase C (PKC) inhibitors, H7 and staurosporine, abrogate IFN-gamma/LPS- and IFN-gamma/IL-1 beta-induced TNF-alpha expression in a dose-dependent manner. PKC activity is required for transcription of the TNF-alpha gene, and does not appear to be involved in TNF-alpha mRNA stabilization. Taken together, these data demonstrate that TNF-alpha gene expression in primary rat astrocytes is induced in a PKC-dependent manner.
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PMID:Role of protein kinase C activity in tumor necrosis factor-alpha gene expression. Involvement at the transcriptional level. 146 Feb 80

The interferon (IFN)-gamma-induced indoleamine 2,3-dioxygenase (IDO) is implicated in the inhibition of intracellular pathogens, e.g. Chlamydia psittaci and Toxoplasma gondii. The intracellular signaling molecules responsible for the induction of IDO gene expression were investigated by the quantitative polymerase chain reaction. The gene expression was inhibited by a tyrosine kinase inhibitor, genistein. Being consistent with this, IFN-gamma induced increased tyrosine phosphorylation and this was inhibited by genistein. The transcription of IDO gene was not inhibited by protein kinase C (PKC) inhibitors, H-7 and staurosporine, or a calmodulin inhibitor, W-7. Irrelevance of PKC in IDO gene expression was supported by the failure of PMA or PMA + A23187 to induce IDO gene expression. These results all suggest that the tyrosine phosphorylation is a critical event in IFN-gamma-inducible IDO gene expression and PKC is not involved in the gene expression.
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PMID:[The signal transduction mechanism responsible for interferon-gamma-inducible indoleamine 2,3-dioxygenase (IDO) gene expression in T98G cells]. 146 78

The IFN-gamma linked PKC activation in endothelial cells was analysed. It was shown that IFN-gamma activates PKC in three transient and separate cycles within the first 60 minutes after IFN-gamma stimulation. Before each PKC activation there was an increase in DAG level. IP3, phosphocholine and choline productions were measured to determine the origin of DAG. Neither of the PLC products, IP3 or phosphocholine, were released after IFN-gamma stimulation. On the other hand the PLD products choline and PA were released before all the three activation cycles of PKC.
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PMID:IFN-gamma induces a phospholipase D dependent triphasic activation of protein kinase C in endothelial cells. 148 78

We have examined the mechanism of synergistic action occurring between interferon (IFN)-gamma and 12-0-tetradecanoylphorbol-13-acetate (TPA) with respect to the reduction of 125I-epidermal growth factor (125I-EGF) binding to human amnion (WISH) cells [Karasaki Y et al (1989) J Biol Chem 264: 6158-6163]. The cells were treated with protein kinase C (PKC) inhibitors (H7, staurosporine) to investigate the role of PKC in the synergism between IFN-gamma and TPA, since TPA is a strong activator of PKC. The combined effect of IFN-gamma and TPA was blocked by the PKC inhibitor, suggesting that PKC plays an important role in the synergistic action of TPA and IFN-gamma on the inhibition of EGF binding to the cells. The prolonged incubation (24 h) of the cells with TPA resulted in the restoration of EGF binding to the cells. A 24 h treatment of WISH cells with both IFN-gamma and TPA, however, still exhibited greater than 50% inhibition of EGF binding. No PKC activity, however, was observed in the WISH cells treated with both IFN-gamma and TPA for 24 h as well as with TPA alone for 24 h, indicating that IFN-gamma may synergize with the second mediator induced by PKC rather than PKC itself in the reduction of EGF binding to WISH cells. In addition, IFN-gamma showed the synergistic action with calcium ionophores on the reduction of EGF binding to the cells, suggesting that Ca2+ may be one of the second mediators which was induced by TPA and which cooperated with IFN-gamma.
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PMID:The mechanism of the action of IFN-gamma and TPA on the modulation of epidermal growth factor receptors of human amnion cells. 162 Oct 11

Activation of the respiratory burst in the monocytic cell line U937 by cross-linking human 40-kDa FcR for IgG (Fc gamma RII) with the IgG1 mAb, CIKM5, is dependent on the maturation state of the cell. Addition of anti-Fc gamma RII to undifferentiated cells does not activate the respiratory burst but differentiation with human rIFN-gamma (200 U/ml) for 13 to 15 days results in maximal stimulation by this agonist, with half-maximal responses in cells incubated for 10 to 12 days. During maturation the development of responsiveness to cross-linking Fc gamma RII occurs later than the development of responsiveness to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (maximal responses at 7 to 9 days), or the chemotactic peptide FMLP (half-maximal responses at 7 to 9 days). The late development of maximal Fc gamma RII responses is not associated with either increased Fc gamma RII expression, enhanced calcium mobilization induced by anti-Fc gamma RII, changes in protein kinase C activity (PKC) or a switch in PKC isotype expression. Activation of the respiratory burst via Fc gamma RII may not be mediated by activation of PKC as the kinase inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride inhibited the Fc gamma RII response by less than 20% at concentrations which inhibit the 12-O-tetradecanoylphorbol-13-acetate-induced respiratory burst by more than 80%. IFN-gamma U937 cells did not metabolize incorporated arachidonate into eicosanoids when stimulated with anti-Fc gamma RII, suggesting that eicosanoids do not mediate activation of the respiratory burst, and this was confirmed by the lack of inhibition by the specific 5'-lipoxygenase and glutathione S-transferase inhibitor, piriprost, and the cyclo-oxygenase inhibitor, indomethacin. In addition there was no significant release of radiolabeled arachidonate in response to anti-Fc gamma RII. The response to anti-Fc gamma RII is inhibited by pertussis toxin, suggesting that signal transduction is via a GTP-binding protein. Agents that elevate intracellular cAMP increased the magnitude of the cAMP transients stimulated by anti-Fc gamma RII and also inhibited the respiratory burst. FMLP responses showed a similar pattern of sensitivity to this range of inhibitors, suggesting that both Fc gamma RII and FMLP receptor share common regulatory mechanisms. However, the termination of the respiratory burst activated via Fc gamma RII and FMLP receptor is independently regulated, in that after FMLP-induced activation there is no subsequent inhibition of the Fc gamma RII-mediated response and vice versa.
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PMID:Differentiation-linked activation of the respiratory burst in a monocytic cell line (U937) via Fc gamma RII. A study of activation pathways and their regulation. 165 5

The effect of SPG on leukocytes has been studied in 20 patients with oral carcinoma and the actions have been analysed in vitro. SPG 1 mg/kg was administered intramuscularly twice weekly. Peripheral venous blood was collected before, and 1 week and 2 weeks after the initiation of SPG treatment. Both CD16+CD57- and CD16-CD57+ cell populations were significantly increased after treatment, but no T cell subset varied. While enhancement of lymphokine-activated killer activity could not be found, an increase in natural killer (NK) activity was observed in 15 of the subjects, and the mean NK level was significantly increased from an initial 34.7 +/- 18.7% to 46.4 +/- 16.5% after two weeks of injections. O2-production by polymorphonuclear leukocytes (PMNL) was stimulated 6 h after SPG injection. When PMNL were treated in vitro with SPG 32 micrograms/ml, enhanced O2-generation was induced and protein kinase C (PKC) activity in a membrane fraction increased. SPG did not directly affect non-specific PMNL killing of K562 cells or antibody-dependent cell mediated cytotoxicity against Raji cells, but non-specific PMNL killing was enhanced by culture-conditioned medium from peripheral blood mononuclear cells (PBMC) containing 10 micrograms/ml SPG. Interleukin-1 beta, -3, -4, -6, tumour necrosis factor-alpha, granulocyte-macrophage colony stimulating factor and IFN-gamma levels in the conditioned medium were not increased compared with medium from PBMC not treated with SPG. No clear increase of these cytokines was found in serum from the SPG-treated patients. From the above results, enhancement of PMNL O2-generation by SPG seems to be a direct action of SPG, but the mechanism of elevation of the non-specific killing activity of PMNL and NK cells is not known. Perhaps other cytokines than those assayed have participated in increasing non-specific cytotoxicity.
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PMID:Immunoregulatory effects of sizofiran (SPG) on lymphocytes and polymorphonuclear leukocytes. 165 62

Recent attention has focused on the role keratinocytes (KC) may play in the induction of T cell-mediated inflammatory responses in skin, particularly because KC, when activated by immunologic stimuli, express MHC class II Ag and secrete immunomodulatory cytokines. We tested the capacity of normal human KC that were stimulated with PMA to induce PBMC proliferation. PMA-treated, but not untreated, KC induced proliferation of allogeneic as well as autologous PBMC; in addition, when purified CD4+ or CD8+ T cells were used as responders, each subset proliferated. PBMC proliferation was not due to direct action of PMA on PBMC, nor to contamination of KC cultures with Langerhans cells (LC) or dermal APC. Pretreatment with different protein kinase C inhibitors abrogated the capacity of PMA-stimulated KC to induce proliferation. Paraformaldehyde-fixed PMA-KC stimulated PBMC proliferation, whereas supernatants from PMA-treated KC failed to do so, indicating that a membrane-associated activity on PMA-KC contributes to the induction of PBMC proliferation. PMA induced intercellular adhesion molecule-1 (ICAM-1) expression on KC; furthermore, mAb against ICAM-1 or against its ligand lymphocyte function-associated Ag (LFA-1) (CD11a/CD18) significantly, but incompletely, reduced the stimulatory capacity of PMA-treated KC, indicating that ICAM-1/LFA-1 interaction contributed to PBMC proliferation. IFN-gamma or TNF-alpha also induced ICAM-1 on KC, but these KC failed to stimulate proliferation, suggesting that PMA induces additional signals from KC, which act in concert with ICAM-1 to promote proliferation. Finally, mAb against HLA-ABC or HLA-DR did not inhibit proliferation. We conclude that PMA can activate KC to stimulate T cell proliferation in a MHC-independent fashion. This activation is mediated by protein kinase C and in part by the induction of ICAM-1 expression on KC.
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PMID:Phorbol myristate acetate-activated keratinocytes stimulate proliferation of resting peripheral blood mononuclear lymphocytes via a MHC-independent, but protein kinase C- and intercellular adhesion molecule-1-dependent, mechanism. 167 Sep 43

Despite the well known interrelationship between the CD2- and CD3-mediated signal transduction pathways, it is not well established whether the CD2 surface expression can be regulated by triggering of TCR/CD3 complex. In this study we show that the stimulation of human PBMC with the Cris-7 (CD3) mAb, both in soluble and particulate form, results in hyperexpression of the CD2 surface Ag, as assessed by immunofluorescence and semi-quantitative immunoprecipitation assays. Similar effects on CD2 surface expression were obtained when different CD3 mAb (OKT3, RW2-8C8 and Leu-4) were tested. The CD3-mediated CD2 up-regulation was suppressed by cycloheximide and actinomycin D, indicating that it requires de novo protein and RNA synthesis. In agreement with this, increased CD2 RNA levels were observed after 3 h of stimulation, reaching a plateau at 24 h that was maintained for 72 h. The CD2 up-regulation was concomitant to other CD3-induced activation-related events such as induction of surface CD25 and CD71 and high RNA levels for c-myc, IL-2R alpha- and beta-chains, CD71, and IFN-gamma. CD2 up-regulation appeared to be elicited by a protein kinase C-dependent mechanism because it was abrogated by staurosporine, a potent protein kinase C inhibitor. Moreover, IL-2-dependent events may also help in enhancing CD2 hyper-expression because it was only partially inhibitable by cyclosporine, dexamethasone, or Mar-108 (CD25) mAb. In conclusion, our data suggest that CD2 up-regulation can be a relevant event in T cell activation triggered by the physiologic engagement of the TCR/CD3 complex.
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PMID:Stimulation through the TCR/CD3 complex up-regulates the CD2 surface expression on human T lymphocytes. 167

Interactions between T lymphocytes, neutrophils, and epidermal cells are believed to play a central role in the pathophysiology of psoriasis and other inflammatory cutaneous disorders. Although there is strong evidence that lymphocyte-function-associated antigen-1 (LFA-1) positive T cells are retained in the epidermis via intercellular adhesion molecule-1 (ICAM-1) expression induced on keratinocytes, the molecular basis for the directed migration of T cells or neutrophils towards the epidermis is not known. To investigate whether epidermal keratinocyte-derived products may be important in the migration of T cells and neutrophils into the epidermis, human keratinocytes were cultured in the presence of various cytokines and chemotactic activity of the supernatants were assessed. TNF-alpha stimulation produced directed migrational responses for both neutrophils and T-lymphocytes (both CD4 and CD8), but not B lymphocytes; 69% of T-cell movement and 80% of neutrophil migration induced by the TNF-alpha treated keratinocyte cell supernatants could be inhibited by anti-interleukin-8 (IL-8) serum. Using the same antibody, IL-8 was immunoprecipitated from the supernatants of TNF-stimulated 35S-labelled keratinocytes, and a single 7-kd band product detected by SDS-PAGE. In keeping with these biological activities and protein data, Northern blot analysis of total cellular RNA extracted from keratinocyte monolayers hybridized with a 32P-labelled 1-kb cDNA to IL-8 mRNA, revealed induction of the IL-8 gene in the presence of TNF-alpha and IL-1 beta, but not IFN-gamma. The protein kinase C agonist, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a known stimulator of psoriasiform cutaneous inflammation when applied directly to murine epidermis, strongly induced keratinocyte elaboration of IL-8 mRNA. These studies demonstrate that activated human keratinocytes are capable of producing biologically active IL-8, and provide evidence that keratinocytes can play a key role in mediating the influx of T cells and neutrophils into the epidermis.
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PMID:Modulation of keratinocyte-derived interleukin-8 which is chemotactic for neutrophils and T lymphocytes. 168 33

The YAC T cell lymphoma normally does not express Ly-6E mRNA or Ly-6E surface molecules but can be induced to do so on incubation with either IFN-gamma or IFN-alpha/beta. This system afforded a model to assess the possible role of protein kinase C (PKC) in IFN-mediated Ly-6E induction. First, we used various pharmacologic agents known to interfere with the function of PKC or other kinases. The PKC inhibitors H-7 and phloretin were found to block Ly-6E induction by IFN-gamma or IFN-alpha/beta both at the mRNA and protein levels. In contrast, inhibitors of cyclic nucleotide-dependent kinases (HA1004), of myosin L chain kinase (ML-9, A-3) or of calmodulin (R24157, W-7) failed to suppress this induction. Next, we investigated the effects of the PKC activators PMA and mezerein (MEZ) on Ly-6E expression. Although neither PMA nor MEZ by themselves could induce Ly-6E in YAC cells, both agents enhanced by up to fivefold the induction of Ly-6 mRNA and Ly-6E surface expression triggered by IFN-gamma. However, the induction of Ly-6E expression caused by IFN-alpha/beta was only marginally increased by cotreatment of YAC cells with PMA or MEZ. Altogether, these observations demonstrate that PKC or a related kinase is involved in the transduction mechanisms that lead to Ly-6E induction. However, activation of PKC is not sufficient for this induction and requires other unidentified signal(s) provided by IFN. Our data also indicate that IFN-gamma and IFN-alpha/beta induce Ly-6E through overlapping but distinct intracellular pathways with different sensitivities to PKC activators.
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PMID:Role of protein kinase C in IFN-mediated Ly-6E antigen induction. 169 61


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