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)

Astrocytes have the ability to secrete colony-stimulating factor 1 (CSF-1), a growth factor known to stimulate the proliferation of brain macrophages. We have studied the effect of cytokines such as interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF alpha), and interleukin 6 (IL-6) on the production of CSF-1 by cultured primary astrocytes and an astrocytic cell line derived from embryonic mouse brain. We observed that both TNF alpha and IL-1 increased CSF-1 mRNA and protein levels in the astrocytic cultures. In contrast, IL-6 was ineffective. The CSF-1 mRNA levels were strongly reduced by incubating immortalized astrocytic cells with staurosporine, a protein kinase C inhibitor, both in the absence and in the presence of cytokines. Conversely, 12-O-tetradecanoylphorbol 13-acetate, a protein kinase C activator, increased CSF-1 mRNA levels. These results suggest a mechanism whereby mononuclear phagocytes could favor their own recruitment in the CNS by producing cytokines.
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PMID:Interleukin 1 and tumor necrosis factor-alpha stimulate the production of colony-stimulating factor 1 by murine astrocytes. 149 7

This review outlines evidence that IL-1, IL-2, and TNFs modulate neutrophil functions. These cytokines affect some or all of the following functions of the neutrophil: adherence, cell migration, respiratory burst, lysosomal enzyme release, and cell surface receptor expression. TNFs, especially TNF alpha, remains one of the most highly studied cytokine with respect to regulation of neutrophil function. TNFs are a direct stimuli for the neutrophil respiratory burst and weak stimuli of lysosomal enzyme release. The cytokines enhance cell adhesion and inhibit neutrophil migration. The TNFs augment the oxidative burst and lysosomal enzyme release response to a wide range of soluble and particulate cell stimuli. These changes in the cell seem to be closely correlated with the increased fungicidal, bactericidal, tumoricidal, and protozoacidal activity of the TNF-primed neutrophils. In contrast to TNFs, IL-1 and IL-2 inhibit neutrophil adherence, and this provides evidence that the cytokine family represents a regulatory system. Another form of regulation of TNF alpha and IL-1 neutrophil-activating activity is by the release of inhibitors to these cytokines (58). We have evidence which shows that the soluble TNF alpha inhibitor (a cleaved product of the TNF alpha receptor) (59) binds and inhibits TNF from activating and priming neutrophils (60). Priming of neutrophils by TNFs involves surface receptor binding but is independent of protein kinase C system, pertussis toxin-sensitive guanine nucleotide regulatory protein, and direct burst of respiratory activity. The translocation of cell surface receptors and constituents of the NADPH oxidase from stored vesicles may be the major mechanism of TNF-induced cell priming.
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PMID:Activation of neutrophils by interleukins-1 and -2 and tumor necrosis factors. 150 43

Protein kinase (PK) C has been implicated in a number of cellular events, many of which are also known to be affected by ethanol (ETOH). ETOH intoxication is also known to impair immune function, thereby increasing the host's susceptibility to infection. The purpose of this study was to assess the effect of acute ETOH intoxication on PKC activity and its intracellular distribution in nonparenchymal liver cells following an E. coli lipopolysaccharide (LPS) challenge. The liver was chosen for the study because it is the primary site both for metabolism of ETOH and detoxification of gut derived bacterial products. Catheterized conscious rats were administered saline or ETOH (175 mg/100 g body weight as a bolus followed by a continuous, 7 hr infusion of 28 mg/100 body weight/hr). LPS was injected intravenously (100 micrograms/100 g body weight) 3 hr before the end of the saline or ETOH infusion. Kupffer and endothelial cells were isolated by collagenase-pronase digestion followed by centrifugal elutriation. PKC was assayed after extraction with digitonin containing buffer and partial purification on DE-52 cellulose minicolumns. LPS decreased PKC activity by 69% from control values. Although ETOH infusion alone did not affect PKC activity in Kupffer cells, it completely abrogated the LPS effect. A similar trend was observed for the endothelial cells. No significant differences were observed between groups with respect to the intracellular distribution of PKC. The down-regulation of PKC by LPS may represent a mechanism of functional adaptation of the immunocompetent cells to one of the cytokines, i.e., TNF, whose receptors are down regulated by activation of PKC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute ethanol intoxication prevents lipopolysaccharide-induced down regulation of protein kinase C in rat Kupffer cells. 155 4

We examined the effects of endotoxin on nitric oxide formation in isolated rat hepatocytes in primary culture. Endotoxin was administered either in vivo, by continuous infusion for 30 or 3 h, or in vitro, on cultured cells. The spontaneous production of nitrites in hepatocytes from in vivo ET-infused rats was lower than equivalent saline controls in the absence of added stimuli. However in vitro addition of endotoxin in culture to hepatocytes from 30 h ET-infused rats greatly enhanced production relative to saline controls. This effect was mimicked by TNF alpha, and activators of protein kinase C (PMA and Ca2+ ionophore A23187). The effects of ET were blocked by NMMA, dexamethasone and protein synthesis inhibitors Actinomycin D and cycloheximide. No in vitro effect of ET was observed in the 3 h infusion model. The results show that chronic exposure to sub-lethal levels of ET primes liver parenchymal cells for the production of nitric oxide, when exposed in vitro to ET or TNF alpha.
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PMID:Endotoxin and TNF alpha directly stimulate nitric oxide formation in cultured rat hepatocytes from chronically endotoxemic rats. 159 81

Human blood monocytes were activated by bacterial lipopolysaccharide endotoxin (LPS) (10 ng/ml) for cytotoxicity of WEHI-164 mouse fibrosarcoma cells, determined by release of 51Cr from WEHI-164 tumour cells incubated with monocyte supernatants. The chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (FMLP) augmented LPS-induced cytotoxicity but had no effect alone. FMLP but not LPS stimulated phospholipase C (PLC), determined by the release of [3H]inositol phosphates. Addition of tumour promoter and protein kinase C stimulant, phorbol-12-myristate-13-acetate (PMA) at concentrations of 3 x 10(-10) M to 3 x 10(-9) M, resulted in an augmentation of 30-200% in LPS-evoked cytotoxicity. The effects of FMLP and PMA, like the effect of LPS alone, were completely blocked by antibody to recombinant human tumour necrosis factor-alpha (TNF-alpha), indicating that cytotoxicity induced by LPS, FMLP, and PMA were due solely to TNF release. Concentrations of PMA greater than 3 x 10(-9) M caused inhibition of TNF release. Okadaic acid (20 ng/ml), an inhibitor of phosphatases I and IIa, augmented the effects of LPS and the stimulatory effects of low levels of PMA, suggesting that phosphorylation was important in the actions of both LPS and PMA. The effects of LPS and of low levels of PMA were augmented by the protein kinase C (PKC) inhibitors H-7 (10-30 microM), staurosporine (2-10 nM) and calphostin C (0.1 microM). Higher concentrations of the inhibitors prevented LPS-evoked TNF release and its augmentation by low levels of PMA. However, they did not prevent the inhibition by high levels of PMA. One possible explanation for the results is that different isozymes of PKC may mediate the stimulatory as compared to the inhibitory effects of PKC on TNF production.
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PMID:Paradoxical stimulation and inhibition by protein kinase C modulating agents of lipopolysaccharide evoked production of tumour necrosis factor in human monocytes. 162

NF-kappa B is a DNA-binding regulatory factor able to control transcription of a number of genes, including human immunodeficiency virus (HIV) genes. In T cells, NF-kappa B is activated upon cellular treatment by phorbol esters and the cytokine tumor necrosis factor alpha (TNF alpha). In the present work, we investigated the molecular events leading to NF-kappa B activation by TNF alpha in a human T cell line (Jurkat) and its subclone JCT6, which presents a deficiency in the PKA transduction pathway. We found that in both cell lines, both phorbol ester and TNF alpha were able to activate NF-kappa B. Phorbol activation was positively modulated by Ca2+ influx while TNF alpha activation was not. Furthermore, while PMA activation was inhibited by the PKC inhibitor staurosporin, the TNF alpha effect was unchanged. TNF alpha did not activate cAMP production and its signal was not modulated by cAMP activators. Moreover, cAMP activators did not activate NF-kappa B in Jurkat cells. Thus, TNF alpha-induced NF-kappa B activation was found to be mediated by none of the major signal-mediating kinases such as protein kinase C (PKC), protein kinase A, or Ca(2+)-regulated kinases. Furthermore, we found that cytoplasmic acidification facilitated NF-kappa B activation by both TNF alpha and PKC, by a mechanism that increases NF-kappa B/I kappa B dissociation without affecting the NF-kappa B translocation step.
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PMID:NF-kappa B activation by tumor necrosis factor alpha in the Jurkat T cell line is independent of protein kinase A, protein kinase C, and Ca(2+)-regulated kinases. 165 56

The second messengers and protein kinases involved in the induction of type I plasminogen activator inhibitor (PAI-1) synthesis by various agents were evaluated in cultured bovine aortic endothelial cells. Phorbol myristate acetate (PMA) induced PAI-1 in these cells implicating the protein kinase C (PK-C) pathway. However, bradykinin, which also activates PK-C in bovine aortic endothelial cells, did not induce PAI-1. Moreover, when PK-C was down-regulated by PMA pretreatment, subsequent induction of PAI-1 by transforming growth factor beta (TGF beta) and tumor necrosis factor alpha (TNF alpha) was unaltered, and induction by lipopolysaccharide (LPS) was decreased by only 50%. LPS increased phospholipid second messengers which can activate PK-C but TGF beta and TNF alpha did not. Agents which increase cAMP, (e.g., forskolin and isobutylmethylxanthine) blocked the induction of PAI-1 synthesis by PMA, LPS, TGF beta and TNF alpha suggesting that induction may occur by lowering cAMP. This possibility seems unlikely since cAMP levels did not change in response to any of these agents. Moreover, somatostatin lowered cAMP but did not induce PAI-1. PAI-1 was not induced by treating the cells with cGMP, Na+/H+ ionophore and calcium ionophore or arachidonic acid.
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PMID:Regulation of type I plasminogen activator inhibitor synthesis by protein kinase C and cAMP in bovine aortic endothelial cells. 165 42

The expression of TNF-alpha receptors (TNFR) was examined on a CD4+ T cell hybridoma, transformed T cell lines, CTL clones, and activated T cells from peripheral blood to determine the basis of the immunomodulatory activity of TNF on T cell function. Analyses by ligand cross-linking and competitive binding assays with mAb to the 80-kDa receptor (TNFR-I), demonstrated that the TNFR-I was the predominant receptor expressed on activated CD4+ and CD8+ T cell subsets. However, on T cell leukemic lines, a second, non-TNFR-I binding site was identified, most likely the 55-kDa form (TNFR-II). Additional subsets of T cells were readily distinguished by their expression of TNFR-I and related members of the TNFR gene family (CD40 and CD27). Expression of the TNFR-I was dependent upon the state of T cell activation. Signaling through the TCR for Ag or IL-2R was sufficient to induce TNFR mRNA and protein expression in resting T cells. Multiple sizes of TNFR-I transcripts were detected during T cell activation; however, biosynthetic studies showed these multiple species encode a single protein of 80 kDa. These results, combined with the known ability of TNF to induce IL-2R expression, indicate that TNF and IL-2 form a reciprocating receptor amplification circuit. In contrast, differentiated effector T cells triggered through the TCR or protein kinase C initiated a rapid down-regulation (transmodulation) of the TNFR-I that preceded TNF or lymphotoxin secretion. The mechanism of transmodulation involved proteolytic processing of the mature 80-kDa receptor releasing a soluble 40-kDa fragment. This indicates that a TNF autocrine loop is not likely to form during the response of an effector T cell. Collectively, these results suggest that transcriptional and post-translational modification of the TNFR-I are important control points regulating the expression of this receptor during T cell activation.
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PMID:Tumor necrosis factor (TNF) receptor expression in T lymphocytes. Differential regulation of the type I TNF receptor during activation of resting and effector T cells. 166 12

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 hepatic response to systemic injury is characterized by a co-ordinated increase in the expression of several, functionally essential plasma proteins. The factors responsible for initial hepatic stimulation have been identified and include the cytokines IL-1 (interleukin-1), tumor necrosis factor alpha (TNF alpha), IL-6 (interleukin-6), hepatocyte-stimulating factor-III (HSF-III) as well as corticosteroids. The absolute level of expression of the regulated proteins appears to be modulated by the pre-existing hepatic hormonal environment and changes to that environment that occur during acute phase reactions. The specific effects of glucocorticoids, IL-1 and activation of protein kinase C are addressed in this study. In order to predict the phenotype of liver response in acute phase, the hepatic activities of all inflammatory cytokines present must be established. Moreover, it must be recognized that the hepatic environment itself can modulate the anabolic response of the liver to these cytokines. The same considerations are needed when determining the changes seen during the progression to chronic inflammation.
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PMID:Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. 169 52


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