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 role of macrophages in the regulation of inflammation and immunity is, in part, due to their secretory repertoire. Among the important mediators released by macrophages are the products of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid (20:4) metabolism. The principal focus of this paper is the mechanism by which bacterial lipopolysaccharides (LPS) regulate 20:4 metabolism in macrophages. LPS has the capacity to prime macrophages for greatly enhanced 20:4 metabolism when the cells are subsequently challenged with a spectrum of triggers. Concomitant with priming, LPS also promotes the covalent attachment of myristic acid to a set of macrophage proteins. The time and concentration dependence of LPS-induced protein myristoylation is consistent with a role for myristoylation in LPS priming of the 20:4 cascade. One of the myristoylated proteins is a 68K (K = 10(3) Mr) protein kinase C substrate which associates with membranes upon myristoylation. LPS-primed macrophages show greatly increased phosphorylation of the 68K protein when the cells are subsequently treated with protein kinase C activating phorbol esters. It is proposed that the myristoylation of the 68K protein promotes its attachment to the membrane where it is more closely associated with activated protein kinase C (PKC), an association which would ensure more efficient catalysis during the mobilization and oxygenation of 20:4. This paper also examines protein myristoylation during T-cell-mediated activation of macrophages. Immune-activated macrophages have an enhanced capacity to kill several infectious agents by oxidative mechanisms. The lymphokine gamma-interferon (IFN gamma) rapidly induces the myristoylation of a 48K protein. This 48K protein is also myristoylated in murine macrophages that have been activated in vivo by intraperitoneal injection of Corynebacterium parvum, suggesting that it may be an important intermediate in the activation of macrophages for enhanced microbicidal capacity.
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PMID:Protein myristoylation as an intermediate step during signal transduction in macrophages: its role in arachidonic acid metabolism and in responses to interferon gamma. 315 94

Both leukotrienes and dibutyryl cyclic GMP can replace the interleukin 2 (IL 2) requirement for gamma-interferon (gamma-IFN) production. In this study, the Ca dependence of the IL 2 help was demonstrated by blockage of gamma-IFN production by the Ca blocker Mn, and the competitive reversal of this block by Ca. Neither leukotriene C4 nor dibutyryl cyclic GMP could reverse the Mn block, which suggests that arachidonic acid release from phospholipids is not the only Ca-dependent event in IL 2 help for gamma-IFN production. A role for calmodulin or protein kinase C in the IL 2-mediated events was suggested by the blockage of gamma-IFN production by chlorpromazine. Relatively high concentrations of Ca were able to replace the IL 2 helper effects. Consistent with this were Ca influx experiments that showed that IL 2 helper signals for gamma-IFN production involved activation of a Ca channel.
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PMID:Interleukin 2-mediated events in gamma-interferon production are calcium dependent at more than one site. 391 81

Macrophage activation for tumoricidal and microbicidal functions can be achieved in part by treatment with recombinant interferon gamma (IFN gamma) in vitro. We have previously demonstrated that IFN gamma treatment of murine peritoneal macrophages results in a two- to five-fold increase in the activity of Ca++, phospholipid dependent protein kinase C (Hamilton et al., J. Biol. Chem., 260:1378, 1985). We now report that this effect was not dependent upon continuing protein synthesis since treatment with cycloheximide under conditions where normal protein synthesis was inhibited by greater than 95% had no effect upon the development of increased enzyme activity. Examination of Ca++ and phospholipid requirements revealed no differences between enzyme isolated from control or IFN gamma treated cells. Similarly, protein kinase C from control and IFN gamma-treated cells could not be distinguished in terms of the diacylglycerol (DG) or phorbol diester (PMA) concentration required for stimulation of activity. Kinetic analysis of the ATP (as substrate) concentration dependence revealed that both control and treated enzyme preparations (either basal or stimulated) had comparable Km values. Maximum velocity (Vmax) was increased both by IFN gamma treatment and also by stimulation with DG or PMA. The major difference which could be discerned between protein kinase C derived from control versus IFN gamma-treated macrophages was the magnitude of the response to DG or PMA; IFN gamma treatment increased the stimulation index (i.e., ratio of basal to stimulated activity) by a factor of two to four fold. These results suggest that IFN gamma treatment leads to reversible modulation of existing protein kinase C resulting in increased catalytic efficiency when exposed to an appropriate stimulant.
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PMID:Characterization of protein kinase C activity in interferon gamma treated murine peritoneal macrophages. 393 82

Experimental results suggest that protein kinase C (PK-C) may play a substantial role in the action of IFNs, but the precise biochemical pathway remains unknown. Recent evidences reveal the complexity of the mechanism of IFN-action and show that the IFN-alpha, -beta and -gamma induced pathways are overlapping. We briefly discuss what is known in this field and suggest a way in which the contrasting views might be reconciled.
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PMID:Signal transducing mechanisms in interferon action (a brief review). 751 32

Vascular smooth muscle cells (SMC) respond by relaxation to nitric oxide (NO) released from the endothelium which expresses a constitutive, Ca(2+)-dependent NO synthase (cNOS). SMC can, however, produce NO themselves upon stimulation by proinflammatory cytokines which induce expression of an inducible, Ca(2+)-independent NO synthase (iNOS). Protein kinase C represents another important second messenger system involved in the regulation of SMC contraction. We have investigated iNOS expression and NO synthesis in rat vascular SMC treated with the cytokines, IFN gamma and TNF alpha, in the presence or absence of the activator of protein kinase C, beta-phorbol-12-myristate 13-acetate (PMA). Treatment with PMA did not induce any significant accumulation of nitrite, a major stable metabolite of NO, in SMC. When added simultaneously with the cytokines, PMA significantly reduced nitrite accumulation induced by cytokine stimulation in a dose-dependent fashion. This inhibitory effect was mediated by activation of PKC since calphostin C, a specific PKC inhibitor, abolished the PMA effect. Further analysis of iNOS mRNA with a rat iNOS cDNA probe demonstrated that addition of PMA reduced expression of SMC iNOS mRNA, indicating that the antagonism in induction of NO synthesis between PMA and the proinflammatory cytokines acts on the transcriptional level. The inhibitory effect of PMA may be mediated via induction of a suppressor of iNOS expression, since pretreatment with PMA reduced NO production after subsequent treatment with cytokines. These observations suggest that activation of the PKC pathway is involved in a negative regulation of iNOS gene expression and this is compatible with the observation that vascular SMC contraction can be induced by PKC activation.
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PMID:Protein kinase C activation inhibits cytokine-induced nitric oxide synthesis in vascular smooth muscle cells. 752 Feb 82

1. In RAW 264.7 macrophages, lipopolysaccharide (LPS) and gamma-interferon (IFN gamma) alone or in combination stimulated the induction of nitric oxide synthase (iNOS) activity and increased the expression of the 130 kDa isoform of NOS. 2. LPS-induced NOS activity was reduced by incubation with CD14 neutralising antibodies and abolished in macrophages deprived of serum. 3. LPS stimulated a small increase in protein kinase C (PKC) activity in RAW 264.7 macrophages which was dependent on the presence of serum. However, IFN gamma did not potentiate LPS-stimulated PKC activity. 4. The protein kinase C inhibitor, Ro-318220, abolished both LPS- and IFN gamma-stimulated protein kinase C activity and the induction of NOS activity. 5. LPS- and IFN gamma-induced NOS activity was reduced by the tyrosine kinase inhibitor genestein. Genestein also reduced LPS-stimulated protein kinase C activity but did not affect the response to the protein kinase C activator, tetradecanoylphorbol acetate (TPA). 6. Nicotinamide, an inhibitor of poly-ADP ribosylation, abolished LPS- and IFN gamma-induced NOS activity. 7. Brefeldin A, an inhibitor of a factor which stimulates nucleotide exchange activity on the 21 kDa ADP-ribosylation factor, ARF, reduced LPS- and IFN gamma-induced NOS activity by approximately 80%. 8. These results suggest the involvement of protein kinase C, tyrosine kinase and poly-ADP ribosylation pathways in the regulation of the induction of nitric oxide synthase in RAW 264.7 macrophages by LPS and IFN gamma.
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PMID:Protein kinase C and tyrosine kinase pathways regulate lipopolysaccharide-induced nitric oxide synthase activity in RAW 264.7 murine macrophages. 753 21

The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.
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PMID:Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. 753 79

Loxoribine is a potent new immunostimulant with a relatively broad spectrum of immunobiological activities. Both loxoribine and its analogues function as agonists of immune responses in a variety of species, including humans. They upregulate the activity of B cells, T cells, NK cells, macrophages, and LAK cells. Induction of enhanced cytokine secretion has been found to involve IFN-alpha/beta, IFN-gamma, TNF-alpha, TNF-beta, IL-1, IL-6, and the 40 kDa chain of IL-12. Evaluation of in vivo activity has been undertaken only for antibody production, NK cell-mediated cytotoxicity, induction of certain cytokines, and LAK cell-mediated cytotoxicity; all four types of activity are markedly upregulated by loxoribine in vivo. Augmentation of antibody production has been observed for protein, recombinant protein, and synthetic peptide antigens, among others. Because loxoribine and its analogues transmit a T-helper-like signal to antibody-producing B cells, it is a highly effective adjuvant even for synthetic peptides that lack T-cell epitopes, effectively replacing the function of T-helper cells in this milieu. It thus provides an alternative, T-cell-independent vaccination strategy if it becomes desirable to avoid untoward T-cell-mediated effects, or in patients with functional or absolute T-cell deficiency. There are a number of features unique to loxoribine that are highly advantageous under specific circumstances: (1) T cell independence; (2) loxoribine augments antibody responses from an intracellular location (rather than at the surface membrane), independently of protein kinase C involvement; this may be particularly relevant for patients with membrane receptor/signal transduction defects; (3) adjuvanticity of loxoribine is essentially free of cytokine dependency; this may be of particular value for organ transplantation patients whose cytokine-dependent immunity is pharmacologically suppressed; (4) loxoribine bypasses functional immunological immaturity, rendering it particularly useful for vaccines in infants. In preclinical safety studies, the drug has exhibited a relatively benign profile. Phase I clinical studies to date have produced no toxicity higher than grade 1. The drug appears to be quite stable, and compares very favorably in direct evaluations with a number of other immunostimulators. A number of clinical trials have been planned for the future.
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PMID:A new approach to vaccine adjuvants. Immunopotentiation by intracellular T-helper-like signals transmitted by loxoribine. 755 Dec 37

Interferon-gamma (IFN gamma) is believed to play a role in the pathogenesis of autoimmune thyroid disease, as it is known to exert diverse effects on thyroid metabolism. These include induction of human leukocyte antigen class II expression, inhibition of gene expression of thyroglobulin and thyroid peroxidase, as well as inhibition of cellular proliferation. However, the mechanism of action of IFN gamma in thyrocytes has not been clearly defined. We studied the action of IFN gamma on the production of inositol phosphates and intracellular Ca2+ mobilization in primary cultures of human thyrocytes using the fluorescent Ca2+ indicator fura-2. IFN gamma increased the production of inositol mono-, bis-, and trisphosphates and caused a dose-dependent increase in intracellular Ca2+ ([Ca2+]i) at 37 C. Preincubation with 12-O-tetradecanoylphorbol-13-acetate, which activates protein kinase C, resulted in the abolition of the IFN gamma response, suggesting that protein kinase C was involved in a negative feedback loop resulting in inhibition of IFN gamma-induced [Ca2+]i rise. Prior release of intracellularly stored Ca2+ with thapsigargin, the microsomal Ca2+ pump inhibitor, also abolished the response of IFN gamma. Mobilization of [Ca2+]i resulted in Ca2+ entry across the plasma membrane, which could be blocked by La3+, the inorganic Ca2+ antagonist. The tyrosine protein kinase inhibitor, genistein, inhibited the production of inositol phosphates and the elevation of [Ca2+]i induced by IFN gamma, but had no effect on ATP, suggesting that tyrosine protein kinase is involved in the signaling transduction of IFN gamma. We conclude that the mobilization of intracellular Ca2+ and the production of inositol phosphates are two important signaling events for the action of IFN gamma in human thyrocytes.
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PMID:Interferon-gamma increases intracellular calcium and inositol phosphates in primary human thyroid cell culture. 758 38

Endothelin (ET)-1 was originally characterized as a potent vasoconstrictor peptide secreted by vascular endothelial cells. It possesses a wide range of biological activities within the cardiovascular system and in other organs, including the brain. Also secreted by endothelial cells, nitric oxide (NO), has recently been identified as a relaxing factor, as well as a pleiotropic mediator, second messenger, immune defence molecule, and neurotransmitter. Most of the data concerning the secretion of these two agents in vitro has been collected from studies on macrovascular endothelial cells. Given the remarkable heterogeneity of endothelia in terms of morphology and function, we have analyzed the ability of brain microvessel endothelial cells in vitro to release ET-1 and NO, which, at the level of the blood-brain barrier, have perivascular astrocytes as potential targets. The present study was performed with immortalized rat brain microvessel endothelial cells, which display in culture a non transformed phenotype. Our data demonstrate that: (1) these cells release NO when induced by IFN gamma and TNF alpha, (2) they constitutively secrete ET-1, and (3) cAMP potentiates the cytokine-induced NO release and exerts a biphasic regulation on ET-1 secretion: micromolar concentrations of 8-Br-cAMP inhibit and higher doses stimulate ET-1 secretion. This stimulation is blocked by EGTA and the calmodulin antagonist W7, but not by protein kinase C inhibitors, suggesting the involvement of the calmodulin branch of the calcium messenger system. These results suggest that cerebral microvessel endothelial cells may participate in vivo to the regulation of glial activity in the brain through the release of NO and ET-1.
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PMID:Nitric oxide and endothelin secretion by brain microvessel endothelial cells: regulation by cyclic nucleotides. 768 20


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