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)

Leukotriene D4 (LTD4) is a major lipid mediator involved in inflammatory and allergic disorders including bronchial asthma. Despite its potent biological activity, little is known about the receptor and intracellular signaling pathways. Here we analyzed the signal transduction mechanisms through LTD4 receptors using human monocytic leukemia THP-1 cells. When these cells were stimulated with LTD4, intracellular calcium concentration was increased and mitogen-activated protein kinase (MAP kinase) was activated severalfold. This activation was inhibited by staurosporine or GF109203X treatment or abolished by protein kinase C depletion. Cytosolic protein kinase Calpha was translocated to the membrane, and Raf-1 was activated by LTD4 treatment in a similar time course. LTD4-induced Raf-1 activation was diminished by protein kinase C depletion in the cells. A chemotactic response of THP-1 cells toward LTD4 was observed which was inhibited by pertussis toxin (PTX) pretreatment. Thus, LTD4 has at least two distinct signaling pathways in THP-1 cells, a PTX-insensitive mitogen-activated protein kinase activation through protein kinase Calpha and Raf-1 and a PTX-sensitive chemotactic response. This cellular signaling can explain in part the versatile activities of LTD4 in macrophages under inflammatory and allergic conditions.
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PMID:Leukotriene D4 activates mitogen-activated protein kinase through a protein kinase Calpha-Raf-1-dependent pathway in human monocytic leukemia THP-1 cells. 947 29

This study was undertaken to investigate the effects of propranolol, IFN-beta, and the protein kinase modulators on IFN-gamma induction of MHC class II antigen expression and cytokine production in THP-1 human monocytic cells. IFN-gamma induced expression of HLA-DR and DQ molecules and secretion of the monokines IL-1 beta and TNF-alpha in THP-1 cells in a time and dose-dependent manner. The effect of INF-gamma on class II HLA antigens was dose-dependently inhibited by IFN-beta. H-7, phloretin, staurosporine as well as GF 109203X are selective enzyme inhibitors of protein kinase C (PKC), down-regulating IFN-gamma induced MHC class II expression and cytokine production. Stimulators of PKC, like PMA, replaced IFN-gamma in the induction of monokines in THP-1 cells, whereas the addition of HA 1004 or arachidonic acid to the culture had no effect on IFN-gamma mediated changes. Blocking of phospholipase D (PLD)-derived diacylglycerol (DAG) formation by propranolol abrogated IFN-gamma increased HLA class II expression and IL-1 beta secretion, but had little effect on IFN-gamma induced TNF-alpha production. These findings appear to suggest that PLD-derived phosphatidate is not the primary source of DAG production in IFN-gamma-induced TNF-alpha secretion, but may be necessary for IFN-gamma-mediated MHC class II induction and IL-1 beta production in human monocytes, whereas phospholipase A2 may not be required for IFN-gamma activation of PKC in the process.
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PMID:Effect of propranolol and IFN-beta on the induction of MHC class II expression and cytokine production by IFN-gamma IN THP-1 human monocytic cells. 954 99

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that has been demonstrated to regulate fat cell development and glucose homeostasis. PPARgamma is also expressed in a subset of macrophages and negatively regulates the expression of several proinflammatory genes in response to natural and synthetic ligands. We here demonstrate that PPARgamma is expressed in macrophage foam cells of human atherosclerotic lesions, in a pattern that is highly correlated with that of oxidation-specific epitopes. Oxidized low density lipoprotein (oxLDL) and macrophage colony-stimulating factor, which are known to be present in atherosclerotic lesions, stimulated PPARgamma expression in primary macrophages and monocytic cell lines. PPARgamma mRNA expression was also induced in primary macrophages and THP-1 monocytic leukemia cells by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Inhibition of protein kinase C blocked the induction of PPARgamma expression by TPA, but not by oxLDL, suggesting that more than one signaling pathway regulates PPARgamma expression in macrophages. TPA induced the expression of PPARgamma in RAW 264.7 macrophages by increasing transcription from the PPARgamma1 and PPARgamma3 promoters. In concert, these observations provide insights into the regulation of PPARgamma expression in activated macrophages and raise the possibility that PPARgamma ligands may influence the progression of atherosclerosis.
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PMID:Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. 963 98

Tumor necrosis factor-alpha (TNF-alpha) is associated with several acute and chronic inflammatory conditions. New therapies directed at inhibiting TNF-alpha will be important in treating pathological processes mediated by TNF-alpha. In this study, we studied and compared the effect of the carbocyclic nucleoside analogue (9-[(1R, 3R)-trans-cyclopentan-3-ol] adenine) with pentoxifylline on modulating TNF-alpha production. The carbocyclic nucleoside analogue inhibited TNF-alpha production in a dose-dependent manner (1 microM-1 mM) by stimulated peripheral blood mononuclear cells and cell lines of both monocyte (THP-1) and T-lymphocyte phenotypes (CEM x 174). The drug potently inhibited TNF production in cells stimulated by endotoxin, the superantigen (staphylococci enterotoxin A), the mitogen (phytohemagglutinin), and the protein kinase C activator (phorbol myristate acetate) with ED50 ranging from 5 to 30 microM. At moderate concentrations, the carbocyclic nucleoside analogue inhibited superantigen (ED50 = 300 microM) and alloantigen (mixed lymphocyte reaction) T cell proliferative responses (ED50 = 150 microM). The involvement of protein kinase C and prostaglandin E2 (PGE2), mediators that regulate TNF-alpha production, was also investigated. Unlike PTX, the nucleoside analogue did not upregulate PGE2 production. The inhibition of TNF-alpha production appeared to be mediated at least partly by PKC, since the nucleoside analogue caused suppression of PKC activity in stimulated cells. The results show that the carbocyclic nucleoside analogue is a TNF-alpha inhibitor that may be appropriate in the therapy of TNF-alpha-associated complications. The suppressive properties of the carbocyclic nucleoside analogue on antigen and alloantigen (mixed lymphocyte reaction) responses may be appropriate in disease conditions in which inhibiting both TNF-alpha and T-cell reactivity is desirable.
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PMID:A carbocyclic nucleoside analogue is a TNF-alpha inhibitor with immunosuppressive action: role of prostaglandin E2 and protein kinase C and comparison with pentoxifylline. 974 53

Human lysosomal acid lipase (LAL) is a hydrolase required for the cleavage of cholesteryl esters and triglycerides derived from plasma lipoproteins. It is shown here that during monocyte to macrophage differentiation, the expression of LAL-mRNA is induced. This induction is dependent on protein kinase C activity and protein synthesis. The cell type-specific increase in LAL expression is further investigated in the THP-1 cell line with respect to transcriptional regulation. The human monocytic leukemia cell line THP-1 differentiates into macrophage-like cells when treated with phorbol esters. In order to determine the cis-acting elements necessary for both basal and phorbol 12-myristate-13 acetate (PMA)-enhanced promoter activity, we performed deletion analysis and reporter gene assays. A PMA responsive element has been identified between -182 bp and -107 bp upstream of the major transcription start site. Gel mobility shift assays demonstrated that binding of Sp1 and AP-2 to the LAL promoter is increased by PMA in THP-1 cells. Co-transfections with expression plasmids for Sp1 and AP-2 further emphasized the important role of these transcription factors in both basal and PMA-enhanced LAL expression. Our data suggest that differentiation dependent increase of lysosomal acid lipase (LAL) expression in THP-1 cells is mediated by a concerted action of Sp1 and AP-2.
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PMID:Transcriptional regulation of lysosomal acid lipase in differentiating monocytes is mediated by transcription factors Sp1 and AP-2. 979 98

p21(WAF1) inhibits cyclin-cyclin-dependent kinase (Cdk) complexes, causing cell cycle arrest. p21(WAF1) contains p53-binding sites in its promoter and expression of p21(WAF1) is induced by functional p53. In the present work, we have studied the role of protein kinase C (PKC) in the induction of p21(WAF1) and show that induction of p21(WAF1) expression can occur by activation of PKC in cells having no p53. Human ovarian carcinoma cells, SKOV-3, lack p53 protein and PMA, a potent activator of PKC, did not induce p53. PMA increased the expression of p21(WAF1) mRNA both in these cells and in other cells which do not contain p53 (THP-1 and U937). Treatment of human embryonic fibroblasts, WI38, with PMA also induced the accumulation of p21(WAF1) without affecting p53 levels. However, PMA did not increase levels of p21(WAF1) mRNA in cells where either the PKC or the mitogen-activated protein kinase pathway was blocked. Furthermore, treatment of cells with various phorbol ester derivatives which activate PKC resulted in the induction of p21(WAF1) in SKOV-3 cells. In contrast, phorbol esters which do not activate PKC failed to induce p21(WAF1) expression. PMA increased the transcriptional rate of p21(WAF1) and activated the transcription of a luciferase reporter gene, controlled by the p21 promoter, in SKOV-3 cells with or without a p53 consensus-binding sequence. By contrast, PMA markedly stabilized p21(WAF1) mRNA; the half-life (t1/2) of p21(WAF1) in PMA-treated cells was >8 h compared with <1 h in untreated cells. These findings provide evidence that the PKC pathway induces expression of p21(WAF1) independently of p53. Our present study also suggests that the accumulation of p21(WAF1) transcripts by PMA occurs mainly at post-transcriptional level.
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PMID:p21WAF1 expression by an activator of protein kinase C is regulated mainly at the post-transcriptional level in cells lacking p53: important role of RNA stabilization. 989 8

Microglial interaction with amyloid fibrils in the brains of Alzheimer's and prion disease patients results in the inflammatory activation of these cells. We observed that primary microglial cultures and the THP-1 monocytic cell line are stimulated by fibrillar beta-amyloid and prion peptides to activate identical tyrosine kinase-dependent inflammatory signal transduction cascades. The tyrosine kinases Lyn and Syk are activated by the fibrillar peptides and initiate a signaling cascade resulting in a transient release of intracellular calcium that results in the activation of classical PKC and the recently described calcium-sensitive tyrosine kinase PYK2. Activation of the MAP kinases ERK1 and ERK2 follows as a subsequent downstream signaling event. We demonstrate that PYK2 is positioned downstream of Lyn, Syk, and PKC. PKC is a necessary intermediate required for ERK activation. Importantly, the signaling response elicited by beta-amyloid and prion fibrils leads to the production of neurotoxic products. We have demonstrated in a tissue culture model that conditioned media from beta-amyloid- and prion-stimulated microglia or from THP-1 monocytes are neurotoxic to mouse cortical neurons. This toxicity can be ameliorated by treating THP-1 cells with specific enzyme inhibitors that target various components of the signal transduction pathway linked to the inflammatory responses.
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PMID:Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins. 992 Jun 56

PMA-induced leukotriene C4 synthase (LTC4S) phosphorylation was investigated over a period of 8 h in a monocytic cell line (THP-1). The level of LTC4S phosphorylation was increased 3-5 fold over a 4 h period decreasing to basal levels after 8 h. This phosphorylation event was found to be specific to THP-1 cells as there was a lack of LTC4S phosphorylation in both COS-7 and K-562 cells, and was also found to be dependent on the cellular confluency. In the presence of specific protein kinase C (PKC) inhibitors, a dose-dependent inhibition of the phosphorylation of LTC4S became evident, an effect not seen with PKA and tyrosine kinase inhibitors. This represents the first direct demonstration of LTC4S phosphorylation in whole cells.
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PMID:Demonstration of cell-specific phosphorylation of LTC4 synthase. 1022 30

The regulation of C1q expression was examined in the human monocytic cell line THP-1. Since these cells can be differentiated into cells with macrophage properties and induced to express C1q, they were used as models for mature human monocyte/macrophages and indirectly microglia. Interferon-gamma (IFN-gamma) and the anti-inflammatory steroid agents dexamethasone and prednisone were powerful stimulators of C1q production, alone or in combination. Interleukin-6 (IL-6) and lipopolysaccharide (LPS) also had significant stimulatory activity. Phorbol myristate acetate, a protein kinase C activator, reduced C1q expression. Four additional classes of pharmacological agents were tested for their effect on C1q secretion. Tacrine, but not indomethacin, cimetidine, or propentofylline, showed activity in inhibiting C1q secretion by IFN-gamma treated THP-1-derived macrophages.
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PMID:Expression and regulation of complement C1q by human THP-1-derived macrophages. 1032 18

Macrophages oxidize low density lipoprotein (LDL) by enzymatic and non-enzymatic mechanisms; however, it is evident that macrophage reduction of transition metals can accelerate LDL oxidation in vitro, and possibly in vivo. Distinct cellular pathways contribute to this process, including trans-plasma membrane electron transport (TPMET), and production of free thiols or superoxide. Here, we explore the role of protein kinase C (PKC) in regulating transition metal reduction by each of these redox-active pathways, in human (THP-1) monocytes. We demonstrate that PKC agonists and/or inhibitors modulate reduction of transition metals by monocytes: both thiol-independent (direct) and thiol-dependent (indirect) pathways for transition metal reduction are enhanced by PKC activation, suggesting a potential strategy for therapeutic intervention.
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PMID:Reduction of transition metals by human (THP-1) monocytes is enhanced by activators of protein kinase C. 1054 82


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