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)

NIH 3T3 cells express the alpha, delta, epsilon and zeta isoenzymes of protein kinase C(PKC). Following stimulation of cells (24 h) with the pro-inflammatory cytokine, interleukin 1beta (IL-1beta), we observed, by Western blotting, a dose-dependent effect on the levels of PKC-epsilon and delta, but not on alpha or zeta. Moreover, time course analysis revealed that the isoenzymes, PKC-delta and epsilon were induced by IL-1beta after 7 h. Again, no change in PKC-alpha or zeta levels after IL-1beta treatment were detected. Incubation with selective PKC inhibitor peptides blocked the PKC-alpha, delta, epsilon and zeta antibodies binding to their respective isoenzyme bands. We also observed that the addition of the tumour-promoting phorbol ester, Phorbol 12-myristate 13-acetate (PMA), downregulated PKC-alpha, delta and epsilon by 7 h in NIH 3T3 cells. PMA did not affect constitutively produced PKC-zeta protein levels even after 24-h treatment. In summary, these results demonstrate that IL-1beta induces protein synthesis of the Ca2+-independent PKC-delta and epsilon isoforms in NIH 3T3 cells. The differences observed here between PKC isoenzymes in response to IL-1beta suggest that each isoenzyme may have a unique role in the signal transduction pathways of IL-1beta and that such isoenzyme may have a unique role in the signal transduction pathways of IL-1beta and that such selective expression may influence the action of agents which require PKC for signal transduction acting in concert with IL-1.
Cytokine 1997 Aug
PMID:Interleukin-1beta-induced expression of protein kinase C (PKC)-delta and epsilon in NIH 3T3 cells. 924 85

Leukaemia inhibitory factor (LIF) acts on the growth and differentiation of haematopoietic cells. By using a specific enzyme-linked immunosorbent assay for human LIF, we demonstrate that human bone marrow stromal cells produce LIF. LIF synthesis is enhanced in a dose-dependent manner after stimulation with lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMAS). LIF production in response to PMA is PKC-dependent since the two PKC inhibitors sphingosine and staurosporine markedly diminished it. Interleukin 1alpha (IL-1alpha), IL-1beta, IL-3, IL-6, IL-8, tumour necrosis factor (TNF-alpha) and SCF (both at 10 ng/ml) stimulate LIF production. By contrast macrophage colony-stimulating factor (M-CSF), granulocyte (G)-CSF, GM-CSF, basic fibroblast growth factor (bFGF), platelet-activating factor (PAF), protaglandin E2 (PGE2), leukotriene B4 (LTB4), and leukotriene C4 (LTC4) did not. These results suggest that bone marrow stromal cells might represent a major source for the cytokine-regulated local production of LIF inside human bone marrow.
Cytokine 1997 Oct
PMID:Spontaneous and inducible production of leukaemia inhibitory factor by human bone marrow stromal cells. 934 7

Tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) are potent inflammatory cytokines produced by osteoblasts and whose contribution to bone loss occurring in oestrogen deficiency is well documented. Calcitonin gene-related peptide (CGRP) is a neuropeptide abundantly concentrated in sensory nerve endings innervating bone metaphyses and periosteum suggesting that it controls bone homeostasis locally. Since CGRP was shown to inhibit TNF-alpha production by T cells and stimulate IL-6 expression by fibroblasts, this study was designed to investigate whether CGRP regulated TNF-alpha and IL-6 production by osteoblasts. We show that CGRP inhibits the production of TNF-alpha by both lipopolysaccharide (LPS)- and IL-1-stimulated fetal rat osteoblasts. Like CGRP, the cAMP agonists prostaglandin E2 (PGE2), dibutyryl cAMP (Bt2cAMP) and forskolin inhibit TNF-alpha production by osteoblasts. Exposure of osteoblasts to a high dose of phorbol myristoyl acetate (PMA) to deplete PKC activity abolished CGRP-mediated TNF-alpha suppression. In contrast with its potent inhibition of TNF-alpha production, we show that CGRP is a weak inducer of IL-6 when compared to PGE2, Bt2cAMP and forskolin. However, in presence of isobutylmethylxanthine (IBMX) CGRP stimulates the production of IL-6. Collectively, these data suggest that the inhibition of TNF-alpha CGRP is cAMP dependent and PMA sensitive and that the concentration of intracellular cAMP may be a regulatory mechanism for IL-6 expression in osteoblasts.
Cytokine 1997 Dec
PMID:The neuropeptide calcitonin gene-related peptide inhibits TNF-alpha but poorly induces IL-6 production by fetal rat osteoblasts. 941 11

Activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) increased steady-state levels of mRNA encoding the major histocompatibility complex (MHC) class II antigen I-A beta and the class II antigen-associated invariant chain (Ii, CD74) in A20 B lymphoma cells and in normal mouse B cells. The increase in Ii mRNA levels appeared to be due to a slight increase in the rate of gene transcription and an increase in the stability of Ii mRNA. The half-life of Ii mRNA increased from 12 h to >24 h following treatment with TPA, as determined by Northern blot analysis following actinomycin D treatment or by the [3H]-uridine pulse-chase method. Interferon-gamma (IFN-gamma), which has been well characterized as a cytokine that induces class II antigens and the Ii, increased Ii expression slightly in A20 cells. However, cotreatment of cells with TPA and IFN-gamma resulted in a block in the TPA-induced increase in Ii expression. Transcription of the Ii gene was minimally affected following treatment with IFN-gamma alone, and cells treated with both TPA and IFN-gamma had the same transcription rate as the control cells. IFN-gamma did, however, block stabilization of Ii mRNA by TPA. Activation of PKC by TPA, which was previously shown to lead to membrane translocation and downregulation, was not inhibited by IFN-gamma. Therefore, IFN-gamma appeared to block a downstream signal transduction pathway activated by PKC that controls stability of Ii mRNA.
J Interferon Cytokine Res 1997 Dec
PMID:Stabilization of invariant chain mRNA by 12-O-tetradecanoylphorbol-13-acetate is blocked by IFN-gamma in a murine B lymphoma cell line. 945 62

Dehydroepiandrosterone (DHEA) alone, whatever the concentration used, or lipopolysaccharide (LPS) alone at 0.2 ng/ml did not induce the release of interleukin-6 (IL-6) or tumor necrosis factor (TNF) by human monocytes. However DHEA (10[-9] M or 10[-12] M) in association with LPS (0.2 ng/ml) did induce the release of IL-6 and TNF. When human monocytes were activated by 1 microg/ml LPS, both IL-6 and TNF secretions were observed. Monocytes activated by both DHEA (10[-9] M or 1O[-12] M) and LPS (1 microg/ml) secreted IL-6 and TNF at a higher level than that observed for monocytes activated only by LPS (1 microg/ml) alone. DHEA alone, whatever the concentration used, or LPS alone at 0.2 ng/ml did not induce the activation of mitogen-activated protein kinases (MAPkinases) and protein kinase C (PKC) or the expression of c-fos and c-jun. However DHEA (10[-9] M or 10[-12] M) and 0.2 ng/ml LPS together induced the activation of both MAPKinases and PKC and the expression of c-fos and c-jun. Furthermore, the activation of PKC and MAPKinases and the expression of c-fos and c-jun were much greater when human monocytes were activated by both LPS (1 microg/ml) and DHEA (10[-9] M or 10[-12] M) than when the monocytes were activated only by LPS at 1 microg/ml. Therefore, DHEA and LPS displayed a synergistic effect on monocyte activation.
J Interferon Cytokine Res 1998 Feb
PMID:Activation of human monocytes by LPS and DHEA. 950 63

By using a specific enzyme-linked immunosorbent assay, the authors demonstrated that human bone marrow stromal cells produce IL-6 and IL-8. Their synthesis is enhanced in a dose-dependent manner after stimulation with lipopolysaccharide (LPS) and phorbol myristate acetate (PMA). Interleukin 6 (IL-6) and IL-8 production in response to PMA were markedly diminished by the PKC inhibitor staurosporine. IL-6 (10 ng/ml) stimulated IL-8 production with 0% and 10% fetal calf serum (FCS) in the culture medium. In similar conditions, IL-8 (10 ng/ml) enhanced IL-6 production. IL-1 alpha, IL-1 beta, and IL-3, tumour necrosis factor alpha (TNF-alpha), Stem cell factor (SCF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (at 10 ng/ml) stimulated IL-6 and IL-8 production in 0% and 10% FCS. G-CSF stimulated and IL-4 inhibited IL-8 production in 10% FCS. IL-2, IL-4 and bFGF stimulated IL-6 production in 0% FCS. These results suggest that bone marrow stromal cells might represent a major source for the cytokine-regulated local production of IL-6 and IL-8 inside human bone marrow.
Cytokine 1998 Feb
PMID:IL-6 and IL-8 production by human bone marrow stromal cells. 951 98

The production of pro-inflammatory cytokines, such as interleukins 1 and 6 and tumour necrosis factors, occurs rapidly following trauma or invasion of the body by pathogenic organisms. The cytokines mediate the wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting, acute phase protein production and immunomodulation. In part, the symptoms result from a co-ordinated response, in which the immune system is activated and nutrients released, from endogenous sources, to provide substrate for the immune system. Although the cytokine mediated response is an essential part of the response to trauma and infection, excessive production of pro-inflammatory cytokines, or production of cytokines in the wrong biological context, are associated with mortality and pathology in a wide range of diseases, such as malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS. Cytokine biology can be modulated by antiinflammatory drugs, recombinant cytokine receptor antagonists and nutrients. Among the nutrients, fats have a large potential for modulating cytokine biology. A number of trials have demonstrated the anti-inflammatory effects of fish oils, which are rich in n-3 polyunsaturated fatty acids, in rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma. Animal studies, conducted by ourselves and others, indicate that a range of fats can modulate pro-inflammatory cytokine production and actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1 production and tissue responsiveness to cytokines, fats rich in n-3 polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids decrease tissue responsiveness to cytokines and IL6 production is enhanced by total unsaturated fatty acid intake. There are a large number of potential cellular mechanisms which may mediate the effects observed. The majority relate to the ability of fats to alter the composition of membrane phospholipids. As a consequence of alterations in phospholipid composition, membrane fluidity may change, altering binding of cytokines to receptors and G protein activity. The nature of substrate for various signalling pathways associated with cytokine production and actions may also be changed. Consequently, alterations in eicosanoid production and activation of protein kinase C may occur. We have examined a number of these potential mechanisms in peritoneal macrophages of rats fed fats with a wide range of fatty acid composition. We have found that the total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal macrophages relates in a positive curvilinear fashion with dietary linoleic acid intake; that TNF induced IL1 and IL6 production relate in a positive curvilinear fashion to linoleic acid intake; that leukotriene B4 production relates positively with dietary linoleic acid intake over a range of moderate intakes and is suppressed at high intakes, while PGE2 production is enhanced. There was no clear relationship between linoleic acid intake and membrane fluidity, however fluidity was influenced in a complex manner by the type of fat in the diet, the period over which the fat was fed and the presence of absence of TNF stimulation. None of the proposed mechanisms, acting alone, can explain the positive effect of dietary linoleic acid intake on pro-inflammatory cytokine production. However each may be involved, in part, in the modulatory effects observed.
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PMID:Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids. 955 30

RNase L (also termed 2-5A-dependent RNase) is a crucial enzyme involved in the molecular mechanism of interferon (IFN) action. Activated by 2',5'-oligoadenylate oligomers (2-5A), this enzyme controls the regulation of RNA stability in IFN-treated or virus-infected mammalian cells. Knowledge of RNase location within cells may provide additional information about its function. Previous work located RNase as a detergent-soluble molecule in nuclei and cytoplasm. In this study, we demonstrate that this enzyme was also present in a detergent-insoluble fraction associated with proteins of the cytoskeleton. A cellular fractionation procedure was used to prepare the cytoskeleton, which was shown to contain 2-5A binding activity not due to cytoplasmic contaminants. In contrast to the cytoplasmic fraction, which contained RNase L with a 2-5A-accessible site, the insoluble RNase molecular form of the cytoskeleton could not be assayed by the classic radiobinding method or the covalent UV cross-linking procedure, which only detects the 2-5A binding site in an open position, that is, free of 2-5A or with an unmasked 2-5A site. The 2-5A binding site present in the cytoskeleton was completely masked and not directly accessible to its 2-5A activator. This particular molecular form of RNase can be detected after a specific denaturing-renaturing treatment of the cytoskeleton, which separates the RNase from cytoskeletal proteins, unmasking the 2-5A site. The cytoskeletal RNase was no longer present at this site when cells were stimulated for a short time with 12-O-tetradecanoylphorbol-13-acetate (TPA). Our data suggest the existence of a pathway that targets the RNase to another subcellular location. To explore the issue further, we examined in vitro the ability of calcium and phospholipid-dependent protein kinase C (PKC) to catalyze significant phosphorylation of the RNase.
J Interferon Cytokine Res 1998 Jun
PMID:Localization of a molecular form of interferon-regulated RNase L in the cytoskeleton. 966 Feb 42

Aged monocytes, that is, monocytes purified from the blood of donors > or =65 years of age, when compared with young monocytes, that is, monocytes purified from the blood of young donors 25 years of age, display a decrease in interleukin-6 (IL-6) and tumor necrosis factor (TNF) production after activation by lipopolysaccharide (LPS). The LPS concentration required to obtain IL-6 and TNF production is much higher for aged monocytes than for young monocytes. Furthermore, the intensity of TNF and IL-6 production was much weaker for LPS-activated aged monocytes than for LPS-activated young monocytes. In addition, deficient protein kinase C (PKC)-alpha, PKC-/betaI, and PKC-betaII activation, deficient mitogen-activated protein kinase (MAP-Kinase) activation, and deficient expression of c-Fos and c-Jun was observed in LPS-activated aged monocytes when compared with LPS-activated young monocytes. These data suggest that age induces human monocyte immune deficiencies that could be observed not only at the functional level but also in the signal transduction pathways.
J Interferon Cytokine Res 1998 Jun
PMID:Signal transduction in LPS-activated aged and young monocytes. 966 Feb 51

Cytokine-induced nitric oxide (NO) is produced on glomerular inflammation. Glomerular injury and thrombocyte aggregation result in the release of nucleotides, which may regulate induced NO synthesis in cultured rat mesangial cells (MCs). ATP (10(-3) M) inhibited 24-h nitrite production induced by lipopolysaccharide (LPS, 10 microg/ml)/interferon-gamma (IFN-gamma, 100 U/ml) by 48.2 +/- 6. 3%, as well as induction of inducible NOS (iNOS) protein and mRNA. Also, coincubation with either 10(-4) M of UTP, ATP, or ATPgammaS inhibited LPS/IFN-gamma-induced nitrite production by 29.9 +/- 5.8, 36.4 +/- 4.3, and 50.3 +/- 6.5%, respectively, indicating involvement of purinergic P2Y2 receptors. Correspondingly, cultured MCs expressed P2Y2 receptor mRNA. Agonists for other purinergic receptors [alpha,beta-methylene-ATP, 3'-O-(4-benzoyl)-benzoyl-ATP, 2-methylthio-ATP, ADP, UDP, adenosine] were ineffective. Treatment with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA, 10(-8) M) reproduced the inhibitory effect of ATP on iNOS protein expression and nitrite inhibition (by 46.6 +/- 10. 4%). The effect of ATP or PMA was reversed by the PKC inhibitors Ro-31-8220 (10(-8) M) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (10(-5) M), indicating that suppression of iNOS is mediated via activation of PKC through stimulated P2Y2 receptors. In conclusion, the release of purine mediators may play a critical role for iNOS expression and synthesis of NO during glomerular inflammatory disorders.
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PMID:Activation of purinergic P2Y2 receptors inhibits inducible NO synthase in cultured rat mesangial cells. 968 11


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