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)

Human eosinophilic cell line EoL-1 was studied using luminol-dependent chemiluminescence (CL) for the ability to produce a respiratory burst upon stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). TPA, a potent activator of protein kinase C, induced a biphasic CL response in EoL-1. Treatment of EoL-1 with interferon-gamma (IFN-gamma) for 5 days dramatically enhanced TPA-inducible CL, and IFN-alpha A had a similar effect. Neither IFN-gamma nor IFN-alpha A strongly inhibited EoL-1 cell growth. Tumor necrosis factor (TNF) also enhanced TPA-inducible CL response of EoL-1 and, furthermore, was quite inhibitory to EoL-1 cell growth. The effects of IFN-gamma and TNF were synergistic, whereas those of IFN-alpha A and TNF were additive. Superoxide dismutase completely abrogated TPA-induced CL, but sodium azide suppressed only the late phase of CL. EoL-1 pretreated with IFN-gamma, IFN-alpha A, or TNF also became capable of producing CL response to a chemotactic peptide (fMLP). The effects of IFN-gamma and TNF were again synergistic. EoL-1 cells treated with IFN-gamma, IFN-alpha A, or TNF had abundant cytoplasm, but only TNF increased cells having distinct eosinophilic granules. IFN-gamma but not IFN-alpha A enhanced the cytological effect of TNF. It was further demonstrated that treatment of EoL-1 with IFN-gamma and TNF strongly increased the binding sites for phorbol diesters and also dramatically induced the surface expression of fMLP receptors. IFN-gamma had, however, little effect on the number or the ligand-binding affinity of TNF receptors on EoL-1. Thus, EoL-1 may provide a useful experimental model for the study of differentiation and regulation of human eosinophils.
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PMID:Membrane oxidative metabolism of human eosinophilic cell line EoL-1 in response to phorbol diester and formyl peptide: synergistic augmentation by interferon-gamma and tumor necrosis factor. 253 64

Treatment of quiescent BALB/c mouse 3T3 cells with murine interferon alpha/beta (IFN-alpha/beta) (1000 units/ml) leads to the appearance at 4 hr of 1.7-kilobase 2',5'-oligoadenylate (2',5'-OAS)mRNA as detected by Northern blot analysis. This mRNA accumulates for at least 18 hr. Two protein kinase C activators, 1,2-dioctanoyl glycerol and phorbol 12-myristate 13-acetate, suppress, whereas the calcium ionophore ionomycin enhances, the IFN-alpha/beta-induced expression of 2',5'-OAS mRNA. The 8-bromo and dibutyryl analogs of cAMP and the adenylate cyclase activator forskolin did not affect the induction of 2',5'-OAS mRNA by IFN-alpha/beta. In the absence of IFN-alpha/beta, the above agents used either singly or in combinations, did not induce 2',5'-OAS mRNA expression nor did platelet-derived growth factor (1-2 units/ml), fibroblast growth factor (6-100 ng/ml), or bovine serum (10-20%). Bovine serum also did not affect 2',5'-OAS mRNA induction by IFN-alpha/beta. The poly(ADP)-ribose synthetase inhibitor 3-aminobenzamide suppressed IFN-alpha/beta-induced 2',5'-OAS gene expression. These results suggest that in quiescent BALB/c 3T3 cells (i) the 2',5'-OAS gene is not responsive to the three major signal transduction pathways activated by diacylglycerol, Ca2+, and cAMP; (ii) induction of the 2',5'-OAS gene by IFN-alpha/beta is decreased by activation of the protein kinase C pathway but enhanced by elevation of intracellular [Ca2+].
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PMID:Signal transduction pathways in the induction of 2',5'-oligoadenylate synthetase gene expression by interferon alpha/beta. 253 38

The biochemical mechanisms involved in the activation and killing of tumor targets by large granular lymphocytes (LGL) have not yet been clearly defined. This laboratory has investigated these processes by analyzing the effects of protein kinase C (PKC) inhibitors (1-(5-isoquinolinesulfonyl)2-methyl-piperazine-dihydrochloride and retinol) on LGL cytotoxicity and IFN-gamma production. We now report that PKC inhibitors block the LGL functions of 1) NK activity, 2) IFN-gamma production, and 3) LAK activity induced by IL-2. Complete inhibition of cytotoxic activity occurs rapidly because only 2.5 h treatment of the LGL with the inhibitors was required. However, the inhibition of NK activity by the PKC inhibitors could be reversed by IL-2 or the synthetic diacylglycerol, L-gamma-1-oleyl-2-acetol-sn-3-glycerol (OAG), but not by IFN-alpha. The reversal of inhibition observed with OAG indicates that, in these studies, (1-(5-isoquinolinesulfonyl)2-methyl-piperazine-dihydrochloride is inhibiting PKC activity and not the activity of other cellular kinases. Furthermore, inhibition of LGL functional activity with PGE2 could not be reversed with OAG, supporting the contention that PG inhibition of NK activity is mediated by a pathway that does not directly involve PKC. These results indicate, in addition to IL-2-mediated events, that basal NK activity is under PKC regulatory control.
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PMID:Modulation of CD3- large granular lymphocyte functions by agonist and antagonists of protein kinase C: effects on NK and lymphokine-activated killer activity and production of IFN-gamma. 254 2

Treatment of human amniotic cells (UAC) with human interferon-alpha (Hu-IFN alpha) or phorbol myristate acetate (PMA) resulted in translocation of protein kinase C (PK-C) activity from the cytosol fraction to that of the membranes. Analysis of 32P incorporation into phospholipid fractions and studies of alterations in fatty acid content for the major phospholipids of IFN-treated cells suggest that phospholipases C and A2 are activated by Hu-IFN alpha. Addition of neomycin (an inhibitor of phospholipase C), as well as mepacrine (an inhibitor of phospholipase A2) to IFN-treated cells inhibited the antiviral activity of Hu-IFN alpha in the vesicular stomatitis virus (VSV)-UAC system used. These observations indicate that (i) activation of PK-C and (ii) diacylglycerol formation, arachidonic acid and/or lysophosphatidylcholine release are important steps in the mechanism of action of IFN.
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PMID:Phospholipase C and phospholipase A2 are involved in the antiviral activity of human interferon-alpha. 254 50

We have investigated control mechanisms of TNF receptor expression (TNF-R) in various human tumor cells and normal peripheral blood monocytes. Activators of protein kinase A (PKA) signal transduction pathways were found to enhance TNF-R expression up to sevenfold, whereas in the same cells, IFN-alpha and -gamma receptors remained unaffected. Inhibitors of protein kinases downregulate both constitutive and cAMP-enhanced TNF-R expression. Binding studies revealed an increase in TNF-R numbers without a change in receptor affinity. Both, direct activators of PKA and inhibitors of phosphodiesterase, raising intracellular levels of cAMP, were found to be effective. As activation of PKA does not slow down the degradation rate of TNF-Rs, but rather enhances protein synthesis-dependent reexpression of TNF-Rs after transient PKC-mediated transmodulation and after tryptic digestion of TNF-Rs, it is concluded that PKA stimulates TNF-R synthesis. Maximum TNF-Rs enhancement is reached after 24 h of stimulation and is reversible, suggesting that receptor upregulation is not linked to irreversible steps of cellular differentiation. PKA-mediated enhancement of TNF-R expression was predominantly observed in normal peripheral blood monocytes and tumor cell lines of myeloid origin. As in these typical TNF producer cells, the production of TNF is also controlled by PKA and PKC, a regulatory circuit is proposed, by which these two independent signal pathways antagonistically regulate TNF production and, at the receptor level, TNF sensitivity.
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PMID:Antagonistic control of tumor necrosis factor receptors by protein kinases A and C. Enhancement of TNF receptor synthesis by protein kinase A and transmodulation of receptors by protein kinase C. 254 68

Recent studies have identified some of the early molecular transductional events, which occur during the activation of murine macrophages. Our current evidence indicate a central role for protein kinase C for the priming effect of interferon-gamma (IFN gamma). IFN gamma also initiates Na+/H+ exchange and 45Ca efflux from murine macrophages (cascade I). Our data further indicate the involvement of multiple transductional pathways in the actions of bacterial lipopolysaccharide (LPS). Specifically, molecular events involved in the action of LPS include production of inositol phosphates and calcium mobilization as well as IFN gamma-regulated alterations in intracellular pH (cascade II). Our data further indicate that additional transductional events (e.g., synthesis of early or competence proteins) in response to LPS (cascade III) are also necessary for macrophage activation. Finally, regulation of important surface (e.g., Ia) and secreted molecules (TNF or IL-1) is exerted at the levels of both transcription and stabilization of specific mRNA in response to transductional cascades I, II and III. Taken together, the data indicate macrophage activation is complexly regulated at multiple levels.
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PMID:Molecular events in the activation of murine macrophages. 265 10

Murine C127 fibroblasts carrying an expression vector for a human interferon gene (HuIFN-beta, under the control of a constitutive promoter) can be induced to produce murine (Mu) IFN by double-stranded (ds) RNA or virus infection. Fibroblasts treated with the protein kinase C activators 1-oleyl-2-acetylglycerol (OAG) or phorbol-12-myristate-13-acetate (PMA) secrete greater amounts of MuIFN than untreated cells, but the same amount of HuIFN-beta. Accordingly, the level of MuIFN-beta mRNA increases in the presence of protein kinase C activators whereas that of HuIFN-beta mRNA is unchanged. In time course experiments after induction with dsRNA, accumulation of MuIFN-beta mRNA is observed within 30 min in the presence of OAG, when this mRNA cannot be detected in control cells. The protein kinase C activators increase accumulation of MuIFN-beta mRNA, even in the presence of the inhibitor of protein synthesis cycloheximide. A similar increase in MuIFN-beta mRNA is observed in C243 fibroblasts treated with phorbol-12-myristate-13-acetate, but not in parental C127 cells. These findings suggest that protein kinase C does not promote synthesis of regulatory factors controlling transcription of IFN mRNA, but that it may be directly or indirectly involved in activation of such factors in some murine cell lines.
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PMID:Activators of protein kinase C enhance accumulation of interferon-beta mRNA in murine cell lines. 279 80

Human monocytes purified by elutriation were cultured for 3 d in Teflon bags with or without human recombinant interferon-gamma (rIFN gamma). The cells were then collected and used in suspension to determine the rate of stimulus-dependent superoxide or hydrogen peroxide formation as a measure of the NADPH-oxidase. The treatment with IFN gamma increased this rate two- to threefold when phorbol myristate acetate (PMA) was used as the stimulus. By contrast, no IFN gamma-dependent increase in superoxide production was observed when the cells were stimulated with different concentrations of the receptor agonist N-formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe) alone or in combination with another receptor agonist, platelet-activating factor (PAF). At optimum concentrations, f-Met-Leu-Phe elicited rates of superoxide formation that could not be exceeded under other stimulatory conditions including PMA after treatment with IFN gamma. It thus appears that f-Met-Leu-Phe can lead to maximum activation of the NADPH-oxidase, and that this response is not influenced by IFN gamma. Treatment with IFN gamma also failed to affect the affinity of PMA- or f-Met-Leu-Phe-stimulated oxidase for NADPH, the Km values being 30 to 40 microM under all conditions. IFN gamma did not alter the cellular levels of cytochrome b558, as measured by low-temperature spectroscopy, and protein kinase C, as measured by [3H]phorbol dibutyrate binding, and did not appreciably influence the stimulus-dependent increase of cytosolic free calcium. These results indicate that activation of human mononuclear phagocytes by IFN gamma does not affect the level and the kinetic properties of NADPH-oxidase or its activation by receptor agonists. They confirm, however, that IFN gamma enhances the respiratory burst response to PMA.
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PMID:Activation of monocytes by interferon-gamma has no effect on the level or affinity of the nicotinamide adenine dinucleotide-phosphate oxidase and on agonist-dependent superoxide formation. 283 24

The number of transferrin receptors in thioglycollate-elicited murine peritoneal macrophages is markedly depressed after exposure to murine gamma-interferon (IFN gamma) in vitro. This change has been used as a model system to study the molecular and cellular mechanisms of IFN gamma signal transduction. We observed that the downshift of the transferrin receptor could be mimicked by exposure to the calcium ionophore (A23187) or the potent tumor promoter, phorbol 12-myristate 13-acetate (PMA). Saturation binding studies on thioglycollate (TG)-elicited peritoneal macrophages after exposure to A23187 or PMA showed the reduced expression of transferrin binding activity attributable to a decrease in the total number of cellular transferrin receptors and not an alteration in receptor-ligand affinity, in agreement with previous results obtained after exposure to IFN gamma. The loss of transferrin receptors in response to A23187 or PMA was dose dependent, and the kinetics of the change were identical to those observed with IFN gamma treatment. Phorbol 12,13-dibutyrate or 4-beta-phorbol 12,13-didecanoate, both biologically active phorbol esters, also induced reduced expression of transferrin receptors, whereas nonesterified phorbol or 4-alpha-phorbol 12,13-didecanoate, an inactive phorbol ester, had no effect on transferrin receptor expression. Finally, PMA and A23187, when used together, acted cooperatively to modulate transferrin receptor expression when both agents were present at subthreshold concentrations. These results, taken together, suggest that elevation of intracellular Ca++ levels and/or stimulation of protein kinase C are involved in the response of macrophages to IFN gamma.
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PMID:Biochemical models of gamma-interferon action: altered expression of transferrin receptors on murine peritoneal macrophages after treatment in vitro with PMA or A23187. 298 Oct 92

Interleukin-2 (IL-2) is a chemically defined lymphokine (LK) available as mixed human (LK) preparations, as partially purified lymphoblastoid IL-2, or as recombinant human IL-2. Each has different actions dependent on companion LKs showing synergistic interaction (e.g., IL-1 and gamma-interferon (gamma-IFN]). IL-2 acts to expand activated T cells; to activate natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytolytic T cells (CTL); to regulate T-cell ontogeny via actions on prothymocytes and immature T cells; and to induce gamma-IFN and activate tumoricidal macrophages. IL-2 acts via specific cell surface receptors on protein kinase C and cyclic GMP-related mechanisms. While stable, its in vivo half-life is short and its persistence is important for it to induce a response. Toxicities include an influenzia-like syndrome, anemia, eosinophilia, and fluid accumulation. In vivo actions include augmentation of cytotoxic responses at high doses, T-cell adjuvant actions, and T-cell restorative actions at midrange doses and at low doses with companion LKs. Antitumor responses in man and animals occur, but irregularly. They are maximized by the concomitant use of LAK cells, cytoreductive therapy, antisuppressor cell therapy, and regional or persistent administration. IL-2 offers hope for more effective therapy of cancer and a variety of immunodeficiency diseases involving IL-2 defects, including AIDS, viral infections, and autoimmune diseases.
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PMID:Recent advances in the preclinical and clinical immunopharmacology of interleukin-2: emphasis on IL-2 as an immunorestorative agent. 314 Oct 54


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