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)

We have examined the ability of human astrocytes to synthesize and secrete leukemia inhibitory factor (LIF), which is a multifunctional cytokine that controls cell proliferation and differentiation in many tissues, including the nervous system. Astrocyte-enriched cultures, prepared from 8- to 9-wk-old embryonic brains, expressed LIF mRNA and secreted LIF protein. LIF synthesis was significantly increased by the cytokines IL-1 beta, TNF-alpha, and TGF-beta 1, but not by IFN-gamma, IL-6, or LPS. No major differences in basal and cytokine-inducible LIF production were detected among astrocyte populations obtained from different brain areas. LIF synthesis was lower in serum-free than in serum-containing astrocyte cultures. A role for protein kinase C in the regulation of astrocyte LIF production was suggested by the findings that phorbol esters induced both LIF mRNA and protein and that the cytokine-induced LIF increase was partially antagonized by relatively selective inhibitors of protein kinase C such as H7 and staurosporine. Human leptomeningeal fibroblasts also expressed LIF gene and protein. Astrocytes produced LIF and responded to cytokines with increased LIF synthesis only after being subcultured, and not when grown in primary cultures in close contact with neurons. Our findings suggest that in vivo induction of astrocyte LIF secretion might occur in pathologic conditions as a consequence of both alterations of neuronal-glial interactions and a local increase in the level of inflammatory cytokines.
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PMID:Regulation of leukemia inhibitory factor synthesis in cultured human astrocytes. 817 20

Activation of protein kinase C with phorbol esters stimulates prostaglandin (PG) biosynthesis in many cell types whereas down-regulation of protein kinase C can suppress stimulatory responses. Interleukin-1 beta (IL-1 beta) can stimulate PG production by intrauterine tissues and may play a significant part in the mechanisms of preterm labor associated with intrauterine infection. Hence we have evaluated the effects of staurosporine and H7 (inhibitors of protein kinase C) on IL-1 beta stimulation of amnion, chorion and decidual prostaglandin E2 (PGE2) production. Staurosporine and H7 alone were without effect on PGE2 production by any cell type. However with minor exceptions both protein kinase C inhibitors enhanced the stimulatory actions of IL-1 beta on PGE2 production by all three cell types. Hence we believe that protein kinase C is closely linked to the regulation of intrauterine PG biosynthesis and that these links may have multiple layers of complexity.
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PMID:Regulation of intrauterine prostaglandin biosynthesis: interactions between protein kinase C and interleukin 1 beta. 820 52

3,4-Diacetoxy benzylidene diacetate (ACP) is a prodrug of protocatechualdehyde (PAL). PAL significantly inhibited interleukin-1 (IL-1) production and release in human monocytes in a dose dependent fashion under lipopolysaccharide (LPS) stimulation. ACP showed inhibitory effects on cartilage destruction of the femoral condyles induced by adjuvant arthritis in vivo in a significant and dose dependent fashion. To clarify the mechanism of action of ACP on rat adjuvant arthritis, we investigated the effects of PAL, a metabolite of ACP, on IL-1 production using synovial cell cultures derived from patients with rheumatoid arthritis. PAL significantly inhibited the IL-1 beta production induced by IL-1 alpha or PMA without inhibition of total protein synthesis and cytotoxicity. A protein kinase C (PKC) inhibitor, staurosporine, also suppressed the IL-1 beta production induced by IL-1 alpha or PMA, suggesting that the PKC pathway plays an important role in IL-1 alpha-induced IL-1 beta production. The calcium ionophore A23187 (A23187) potentiated the IL-1 beta production induced by IL-1 alpha. Whereas PAL slightly inhibited under these conditions, it was not statistically significant. These results suggest that PAL has a favourable action on cartilage destruction through the inhibition of IL-1 production induced by the modification of the PKC pathway.
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PMID:Effect of a benzylidene derivative, a novel antirheumatic agent, on IL-1 production. 823 46

The regulation of IL-6 mRNA expression was studied in human blood monocytes and in the human epidermoid carcinoma cell line HEp-2. In human monocytes phorbol-12-myristate 13-acetate (PMA) did not induce IL-6 but it increased IL-1 beta and IL-8 mRNA levels. Furthermore, in monocytes, protein kinase C (PKC) activation by PMA even reduced IL-1-induced IL-6 mRNA, and IL-1-induced IL-6 synthesis was increased by the PKC inhibitor staurosporine. IL-6 synthesis in HEp-2 cells was induced by IL-1, PMA, and calcium ionophore A 23187 but not by dibutyryl-cAMP. PMA-, but not IL-1-induced IL-6 synthesis in HEp-2 cells was inhibited by staurosporine. PMA pretreatment of HEp-2 cells abolished PMA-induced IL-6 but the IL-1 effect was not reduced. These data indicate that IL-6 can be induced by a PKC-independent pathway in monocytes and HEp-2 cells. In monocytes PKC activation does not induce IL-6 and PMA interferes with the IL-1 effect. Transcription factors known to be involved with the regulation of IL-6 expression were studied by gel retardation assays. NF-IL-6 and AP-1 activity were constitutively expressed in monocytes and HEp-2 cells under conditions where IL-6 mRNA was not detectable and levels did not change in response to stimulation by IL-1 or PMA. In contrast, NF-kB was increased by both IL-1 and PMA, but only the effect of PMA, and not that of IL-1, was inhibited by staurosporine. In summary, these results show tissue-specific differences in the regulation of IL-6 expression. Induction of IL-6 in monocytes is PKC independent. In the epithelial cell line HEp-2 IL-6 is inducible by PKC as well as by a PKC-independent pathway.
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PMID:Regulation of interleukin-6 (IL-6) expression: evidence for a tissue-specific role of protein kinase C. 824 77

Superantigens including staphylococcal enterotoxins (SE) bind to major histocompatibility complex class II molecules and interact with T cells bearing particular V beta chains. SEB was shown to induce the expression of interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha genes in human peripheral blood monocytes bearing HLA class II molecules. Monoclonal antibodies directed against HLA-DR and -DQ abolished the SEB-induced expression of both the IL-1 beta and TNF-alpha genes, suggesting that the HLA class II molecules mediated the gene expression. Therefore, we investigated the signal transduction mechanism responsible for the expression of IL-1 beta and TNF-alpha genes induced by binding of SEB to the HLA class II molecules. Three protein tyrosine kinase (PTK) inhibitors, genistein, herbimycin A, and tyrphostin, each of which has a different mechanism of action, strongly inhibited the expression of the monokine mRNA induced by SEB. Analyses of PTK activity revealed that SEB induced a rapid increase of membrane-associated PTK activity and this was blocked by tyrphostin. Furthermore, H-7 inhibited the expression of the monokine mRNA induced by SEB, suggesting the involvement of protein kinase C (PKC) in the signaling pathway. The involvement of PKC was confirmed by the observations that phorbol 12-myristate 13-acetate (PMA), a direct activator of PKC, induced the expression of the monokine mRNA and that SEB evoked the activation of membrane-associated PKC. Both activation of PKC and expression of the monokine mRNA induced by SEB appeared to be inhibited by tyrphostin, but those induced by PMA were not. Taken together, these findings indicate that both PTK and PKC play essential roles in HLA class II molecule-mediated signal transduction elicited by SEB and that PTK activation may precede PKC activation in the signaling pathway.
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PMID:HLA class II molecule-mediated signal transduction mechanism responsible for the expression of interleukin-1 beta and tumor necrosis factor-alpha genes induced by a staphylococcal superantigen. 825 34

Bacterial LPS induce production of cytokines such as IL-1, IL-6, and TNF in mononuclear phagocytes, and this represents a central component in the pathogenesis of septic shock syndrome. However, the mechanisms by which LPS activates these cells to express cytokines are not completely characterized. The present study addressed the role of different protein kinases in the LPS induction of cytokines. It is shown that LPS induced a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels, and this was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. Protein kinase C inhibition by staurosporine reduced LPS induction of TNF-alpha, whereas it had no effects on IL-6 and IL-1 beta. Inhibition of protein kinase A by H89 reduced IL-6 mRNA levels but did not detectably change IL-1 beta or TNF-alpha mRNA levels. In contrast, LPS did not increase leukemia inhibitory factor mRNA, which was constitutively expressed and not significantly reduced by these inhibitors. In addition to cytokine mRNA levels, LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha. The activation of NF-kappa B was also reduced by H89, whereas staurosporine had no effect on this response. In summary, these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines, whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF-kappa B activation in monocytes.
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PMID:Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. 825 85

Staphylococcal exotoxins (SE) bind to MHC class II molecules and induce the production of IL-1 beta and TNF-alpha in human monocytic cells. Here we show that stimulation of peripheral blood monocytes with toxic shock syndrome toxin-1 (TSST-1) induced rapid increase in tyrosine phosphorylation of cytosolic protein substrates, accumulation of inositol phosphates, and de novo tyrosine phosphorylation of the PLC-gamma 1 isozyme. Accumulation of inositol phosphates was inhibited by preincubation of cells with inhibitors of protein tyrosine kinases (PTK). Stimulation of monocytes with TSST-1 furthermore led to activation of protein kinase C (PKC). PTK and PKC activation plays a role in the induction of monokine gene transcription by SE because inhibitors of PTK and PKC reduced TSST-1-stimulated IL-1 beta and TNF-alpha gene expression. We therefore propose a model in which the induction of monokine gene transcription by TSST-1 in monocytes necessitates activation of tyrosine kinase(s) and of PKC, the latter probably by way of PLC-gamma 1.
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PMID:Early activation events induced by the staphylococcal superantigen toxic shock syndrome toxin-1 in human peripheral blood monocytes. 829 29

It is believed that induction of cytokine expression by bacterial cell wall components plays a role in the development and course of sepsis. However, most attention has been focused on lipopolysaccharide (LPS). We studied the ability of N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D- isoglutamyl-m-diaminopimelyl-D-alanine (G(Anh)MTetra), a naturally occurring breakdown product of peptidoglycan that is produced by soluble lytic transglycosylase of Escherichia coli, to induce cytokine expression in human monocytes. G(Anh)MTetra was found to strongly induce interleukin (IL)-1 beta and IL-6 mRNA expression after 2 h and IL-1 beta and IL-6 protein secretion after 48 h of activation. The increase in mRNA accumulation was at least partly due to an increase in the transcription rates of the respective genes and was accompanied by a strong induction of nuclear factor-kappa B and activator protein-1 transcription factor expression. Experiments using inhibitors of protein kinase C, protein kinase A, and tyrosine kinase-dependent pathways revealed that G(Anh)MTetra-induced IL-1 beta and IL-6 mRNA expression involves activation of an H7-inhibitable pathway. By using the protein synthesis inhibitor cycloheximide, it was shown that G(Anh)MTetra-induced IL-6 mRNA expression depends on the synthesis of new protein, whereas G(Anh)MTetra-induced IL-1 beta mRNA accumulation does not. When responses to G(Anh)MTetra were compared with those to LPS and muramyldipeptide (MDP), it was found that the optimal response to G(Anh)MTetra induction was similar to that of LPS but significantly higher than the response to MDP. Furthermore, maximal G(Anh)MTetra-induced IL-1 beta and IL-6 mRNA expression could be enhanced by co-stimulation with LPS or MDP, suggesting that different receptors and/or transduction pathways were involved. These results indicate that G(Anh)MTetra induces IL-1 beta and IL-6 expression in human monocytes suggesting a possible role for G(Anh)MTetra in the release of cytokines during sepsis.
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PMID:G(Anh)MTetra, a natural bacterial cell wall breakdown product, induces interleukin-1 beta and interleukin-6 expression in human monocytes. A study of the molecular mechanisms involved in inflammatory cytokine expression. 830 82

For the optimal growth of clonogenic cells in acute myeloblastic leukemia (AML), several cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 are required in addition to colony-stimulating factor (CSF), which may be produced by blast cells themselves. In the present study, we addressed the potential role of endogenous production of TNF-alpha and/or IL-1 in the in vitro growth of AML clonogenic cells supported by IL-3. Addition of a specific neutralizing antibody against TNF-alpha (anti-TNF-alpha) to the culture significantly reduced the growth-stimulating effect of IL-3 on the cells in 11 of 14 patients. Simultaneous addition of anti-IL-1 alpha and anti-IL-1 beta also partly affected the growth, although to a much lesser extent when compared to the effect observed with anti-TNF-alpha. In 3 patients, the growth-stimulating effect of IL-3 was completely abrogated by anti-TNF-alpha or a combination of all three antibodies. Constitutive TNF-alpha transcript was observed in 5 patients and TNF-alpha protein was present in culture supernatant. Following in vitro culture, a transient but profound increase in c-fos, c-jun, TNF-alpha and IL-1 beta mRNA levels was observed. Anti-TNF-alpha inhibited the accumulation of TNF-alpha transcript, suggesting that membrane-integrated TNF-alpha may be partly responsible for the induction of TNF-alpha mRNA. It seems likely that the accumulation of these genes occurs through a protein kinase C-independent signaling pathway.
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PMID:Growth potentiating activity of endogenous production of interleukin-1 and tumor necrosis factor alpha in blast cells of acute myeloblastic leukemia. 831 77

The signal transduction pathways leading to the expression of IL-1 beta in human monocytes via HLA-DR stimulation were investigated. SEB, a staphylococcal enterotoxin that binds to HLA-DR molecules, induced IL-1 beta expression in human monocytes. Protein synthesis inhibition by cycloheximide did not inhibit SEB-mediated IL-1 beta signal, indicating that protein synthesis is not required for the MHC class-II-mediated IL-1 beta expression. The effect of PKC, PKA, and tyrosine kinase inhibitors on HLA-DR-mediated IL-1 beta mRNA expression was then determined. H7, a preferential PKC inhibitor, completely inhibited IL-1 beta signal induced by SEB. The role of PKC on HLA-DR-mediated IL-1 beta induction was further confirmed by the ability of SEB to activate PKC on monocytes directly when measured with labeled phorbol ester ([3H]Pbt2)-binding capacity of whole cells. HA 1004, a preferential PKA inhibitor, and isobutyl-methyl-xanthine (IBMX), which inhibits the degradation of cAMP, had no effect on SEB-induced IL-1 beta signal, excluding the role of cAMP on HLA-DR-mediated IL-1 beta expression. Two tyrosine kinase inhibitors, genistein and dihydroxycinnamate, both inhibited SEB-induced IL-1 beta mRNA in monocytes. SEB also induced enhanced tyrosine phosphorylation of several proteins in human monocytes when determined with antiphosphotyrosine immunoblotting. Our results demonstrate that both PKC and protein tyrosine kinases are involved in HLA-DR-induced IL-1 beta expression in human monocytes.
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PMID:Signal transduction mechanisms of HLA-DR-mediated interleukin-1 beta production in human monocytes. Role of protein kinase C and tyrosine kinase activation. 834 Feb 34


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