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)

In this study, we examined the effect of TNF-alpha on mesangial cell gene expression of M-CSF, a colony-stimulating factor associated with monocyte differentiation into macrophages and proliferation. Incubation of mesangial cells with TNF-alpha-stimulated mRNA expression and protein synthesis of M-CSF. Mesangial cell activation with PMA, a PKC activator, stimulated M-CSF mRNA expression while PKC depletion decreased M-CSF mRNA expression to control levels. Stimulation of PKC-depleted mesangial cells with either PMA or TNF-alpha inhibited M-CSF mRNA transcripts. Preincubation of mesangial cells with calphostin C, a PKC inhibitor, reduced both PMA- and TNF-alpha-induced M-CSF mRNA transcripts. Specific protein tyrosine kinase inhibitors blocked TNF-alpha-induced mesangial cell M-CSF mRNA expression. Additional studies showed that pertussis toxin, isoproterenol, and dibutyryl (db)cAMP did not induce mesangial cell M-CSF gene expression. However, coincubation of mesangial cells with TNF-alpha and either dbcAMP, forskolin, or pertussis toxin inhibited TNF-alpha-induced M-CSF gene expression. Finally, TNF-alpha-activated mesangial cell conditioned media stimulated monocyte/macrophage proliferation dose-dependently and was prevented by using anti-M-CSF. These data suggested that M-CSF can regulate monocyte differentiation into macrophages and proliferation within the mesangium induced by proinflammatory cytokines such as TNF-alpha. These cellular events appeared to be modulated by signal transduction pathways mediated by PKC and PTK.
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PMID:Activation of mesangial cells with TNF-alpha stimulates M-CSF gene expression and monocyte proliferation: evidence for involvement of protein kinase C and protein tyrosine kinase. 878 64

Macrophage colony-stimulating factor (M-CSF) is a keratinocyte-derived cytokine whose function in skin is not completely clarified. We investigated its effects on Langerhans cells by examining the amount of IA beta mRNA, beta-actin mRNA and rRNA per cell, and compared them with the effects of other cytokines such as granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha). After culture for 24 h in the absence of exogenous cytokines, rRNA in Langerhans cells decreased steeply while beta-actin mRNA increased. IA beta mRNA also decreased sharply. These decreases in the amount of rRNA and IA beta mRNA were limited when cytokines were added to the culture medium (in order of efficiency M-CSF > GM-CSF > TNF-alpha), but M-CSF was less potent than GM-CSF in up-regulating beta-actin mRNA (GM-CSF > M-CSF, TNF-alpha). The effect of M-CSF, but not that of GM-CSF, was restricted by simultaneous treatment of cells with TNF-alpha. None of these effects engendered a change in the viability of the Langerhans cells in a 24-hr culture. Reverse-transcribed polymerase chain reaction analysis demonstrated that c-fms, the gene of the M-CSF receptor, was expressed in Langerhans cells, implying the physiological importance of M-CSF in vivo. A protein kinase C activator, TPA, up-regulated the amount of IA beta mRNA, while a protein kinase C inhibitor, H-7, suppressed the effects of all three cytokines. These results suggest that M-CSF, in conjugation with TNF-alpha and GM-CSF, plays an important role in controlling the physiological state of Langerhans cells, probably through the activation of protein kinase C.
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PMID:Macrophage colony-stimulating factor (M-CSF) inhibits the decrease in the amount of rRNA and IA beta mRNA in cultured epidermal Langerhans cells of the mouse. 883 32

The activation of macrophages interferes with their response to macrophage colony-stimulating factor (M-CSF), the main growth and differentiation factor for mononuclear phagocytes. We tested the rapid effects of interleukin-4 (IL-4), the alternative macrophage activator produced by Th2 helper lymphocytes, on the receptor for M-CSF (M-CSFR) expressed on the cell surface of murine macrophages. IL4 rapidly down-modulated M-CSFR in a dose-dependent fashion. This effect was unique to IL-4 among a number of Th2-produced cytokines, none of which, with the exception of IL4 itself, is able to activate macrophages. The down-modulation of M-CSFR by IL4 was partially prevented by the inhibition of the activity of phospholipase C or protein kinase C. The data are consistent with the hypothesis that the down-modulation of M-CSFR is a property common to, and exclusive of, macrophage activators, and is driven by different activators via a common mechanism.
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PMID:Interleukin-4 rapidly down-modulates the macrophage colony-stimulating factor receptor in murine macrophages. 892 56

Vascular smooth muscle cells (SMC) transform to foam cells in the process of atherosclerosis. We have reported that SMC derived from the intima of atherosclerotic lesions express c-fms, macrophage colony-stimulating factor receptor gene, which is not normally expressed in medial SMC. In the present study, we demonstrated that transforming growth factor-beta (TGF-beta) synergistically induced expression of c-fms in the presence of platelet-derived growth factor-BB in human medial SMC, a level comparable to that observed in the intima. The induction of c-fms was not inhibited by protein kinase C (PKC) inhibitor, suggesting that TGF-beta induces c-fms via a PKC-independent pathway. These results suggest that TGF-beta plays an important role in the phenotypic change of smooth muscle cells to macrophage-like cells in the process of atherosclerosis.
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PMID:Synergistic effects of transforming growth factor-beta on the expression of c-fms, macrophage colony-stimulating factor receptor gene, in vascular smooth muscle cells. 898 46

It has been recently shown that CSF-1 enhanced the constitutive expression of the Il6 gene in resident mouse peritoneal macrophages (PM phi) but little is known about the pathways involved. In this report, we show that both constitutive and CSF-1-induced IL-6 release were enhanced and prolonged in the presence of the PKC inhibitors, staurosporine (SP) and its derivative, GF-109203X. Enhancement of constitutive IL-6 release required higher concentrations of inhibitors, while enhanced CSF-1-induced release was diminished when inhibitor concentrations exceeded defined limits. SP was also shown to activate constitutive IL-6 release by blood monocytes and elicited PM phi but had no effect on their responsiveness to CSF-1. Activation of PKC by exposure of resident PM phi to phorbol myristate acetate (PMA) also resulted in enhanced IL-6 release and PMA was shown to synergize with CSF-1. These data indicate that CSF-1 does not induce Il6 gene expression by amplifying the constitutive pathway in all mononuclear phagocyte subpopulations. It exerts its effects independently of PKC, which may activate Il6 gene expression in its own right by an alternative pathway. While CSF-1 and PKC are involved in separate pathways, the synergistic IL-6 response seen when PMA and CSF-1 interact suggests convergence of the two pathways. It is also apparent that multiple PKs, excluding PKC, may be involved in repressing constitutive and CSF-1-induced Il6 gene expression.
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PMID:CSF-1-induced and constitutive Il6 gene expression in mouse macrophages: evidence for PKC-dependent and -independent pathways. 916 24

Bryostatin 1 (bryo1), a naturally occurring macrocyclic lactone derived from the marine bryozoan Bugula neritina is a potent protein kinase C (PKC) activator. In this report, we investigated the role of c-fyn protein, a src-related protein tyrosine kinase (PTK), during bryo1-induced monocytic differentiation in a human leukemia cell line, THP-1. Bryo1 treatment for 24 h inhibited the proliferation of THP-1 cells and caused a major fraction of them to become adherent cells with distinct monocyte/macrophage features and enhanced expression of M-CSF receptors (M-CSFR), a hallmark of mature macrophages. The THP-1 cells in control cultures expressed low but detectable levels of c-fyn proteins. Treatment of THP-1 cells with bryo1 resulted in an enhanced expression of c-fyn proteins, but not c-lyn proteins, another member of the src-family of kinases. The bryo1 treatment also enhanced the levels of both c-fyn tyrosine kinase and autophosphorylation activities in THP-1 cells. Using a combined immunoprecipitation and immunoblot analysis, bryo1 was shown to promote an enhanced association between c-fyn kinase and M-CSFR. The inducing activity of bryo1 was associated with PKC activation; treatment of THP-1 cells with bryo1 led to a rapid and transient elevation of total PKC activity in THP-1 cells. These results show that enhanced expression and activation of fyn kinases are critical events associated with monocytic differentiation induced by bryo1 in THP-1 cells. Our findings may be of clinical relevance, as bryo1 has been used in clinical trials of cancer patients.
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PMID:Bryostatin 1 (bryo1)-induced monocytic differentiation in THP-1 human leukemia cells is associated with enhanced c-fyn tyrosine kinase and M-CSF receptors. 922 66

We investigated the role of fyn kinase on the expression of macrophage colony-stimulating factor (M-CSF) receptors (M-CSFR) and macrophage differentiation using a human myelomonocytic leukemic cell line THP-1. Treatment of THP-1 cells with Bryostatin 1 (bryo 1), a potent protein kinase C (PKC) activator, caused a major fraction of them to become adherent (AD) with distinct monocyte/macrophage characteristics. The differentiation was associated with an enhanced expression of M-CSFR and fyn tyrosine kinase activity, occurring primarily on cells in the AD fraction. Scatchard plot analysis showed that the enhanced expression of M-CSFR binding activity was due to an increase in total receptor number per AD cell, rather than an increase in the binding affinity. Fyn antisense (AS) phosphorothioate oligonucleotides (s-oligos) inhibited the up-regulation of both M-CSFR and c-fms transcripts in bryo 1-treated THP-1 cells. In contrast, fyn sense s-oligos did not affect the up-regulation of either M-CSFR or c-fms mRNA in bryo 1-treated cells. In addition, fyn AS s-oligos blocked the expression of AD capacity in bryo 1-treated THP-1 cells. The efficacy of fyn AS s-oligos as macromolecular inhibitors was verified by their ability to lower fyn-associated tyrosine kinase and in vitro autophosphorylation activity in bryo 1-treated THP-1 cells. Taken together, our results show a strong correlation between M-CSFR expression and monocytic differentiation in THP-1 cells, and suggest a possible role of c-fyn tyrosine kinase in mediating these processes.
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PMID:Induction of macrophage colony-stimulating factor receptor up-regulation in THP-1 human leukemia cells is dependent on the activation of c-fyn protein tyrosine kinase. 927 65

Recent data have indicated that resident mouse peritoneal macrophages (PMo) transcribed the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes in response to stimulation with the monocyte-macrophage colony-stimulating factor (CSF-1) but only Il6 mRNA was translated into secreted protein. In this paper, we extend these observations. It is shown that resident PMo incubated with protein kinase (PK)C inhibitors, staurosporine (SP) and its derivative GF109203-X, showed a several fold increase in the levels of Il6 mRNA in control and CSF-1-primed PMo and a parallel release of large amounts of protein. In contrast, SP was shown to have no effect on the release of GM-CSF from control or CSF-1-primed PMo, although it increased by approximately twofold the amount of Csfgm mRNA in CSF-1-primed Mo. When SP was added 4 h after CSF-1 priming to block CSF-1-induced protein kinase pathways, an increased amount of IL-6 release was again seen but without any increase in Il6 mRNA levels. Under these conditions, Csfgm gene expression was relatively unaffected. Activation of PKC by phorbol myristate acetate (PMA) also resulted in increased Il6 gene expression by control and CSF-1-primed PMo. PMA had no apparent effect on Csfgm transcription but appeared to influence translation at a low level, as measured by the release of small amounts of GM-CSF protein. The addition of lipopolysaccharide (LPS) to CSF-1-primed PMo resulted in a synergistic increase in the expression of both genes at the levels of transcription and protein release. The addition of SP to CSF-1-primed Mo before LPS, however, further enhanced IL-6 release but not GM-CSF release from the cells. The data indicate that CSF-1-priming drives a number of pathways involved in the regulation of expression of both genes and renders PMo highly susceptible to appropriate secondary stimulatory agents that transform the PMo into secretory inflammatory cells.
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PMID:Priming of mouse macrophages with the macrophage colony-stimulating factor (CSF-1) induces a variety of pathways that regulate expression of the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes. 928 58

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.
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PMID:Spontaneous and inducible production of leukaemia inhibitory factor by human bone marrow stromal cells. 934 7

Activation of the respiratory burst imposes acute metabolic demands on phagocytic cells. These are met by mobilizing internal energy stores and by increasing the utilization of exogenous energy, including glucose in the circulation. To determine whether the increased glucose uptake that is known to be associated with the respiratory burst involves the regulation of glucose transporter molecules, the intrinsic transport properties of glucose transporters on the macrophage cell line RAW 264.7 were determined after activation with PMA, N-formyl-methionine-leucine-phenylalanine (fMLP) and the cytokines granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3). Treatment with PMA resulted in a 2-fold increase in respiratory burst activity within 10 min; this was associated with a 30-50% increase in 2-deoxyglucose uptake and a 4-fold increase in transporter affinity for glucose. Similarly, fMLP, GM-CSF and IL-3 treatments stimulated 2-deoxyglucose uptake that was associated with a 3-4-fold increase in transporter affinity for glucose. To determine whether the changes observed in 2-deoxyglucose uptake in response to PMA, fMLP and growth factors were influenced by phosphorylation of the sugar, 3-O-methylglucose, which is not phosphorylated, was used. Increased 3-O-methylglucose uptake and increased transporter affinity for glucose were also observed after PMA, fMLP and GM-CSF treatments. Whereas both fMLP and GM-CSF stimulated superoxide production, IL-3 failed to activate respiratory burst activity. The protein kinase inhibitors genistein and staurosporine inhibited the increase in 2-deoxyglucose uptake observed with fMLP and GM-CSF, and partly reversed the affinity increase towards that of untreated control cells. In contrast, the phosphatidylinositol 3-kinase inhibitor wortmannin had little effect on 2-deoxyglucose uptake in response to these activators. Western blotting with subtype-specific antisera showed that Glut-3 was the predominant transporter on RAW 264.7 cells. These studies demonstrate that acute regulation of glucose transporters occurs in response to activators that promote respiratory burst activity, and show that this regulation involves both tyrosine kinases and protein kinase C activity.
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PMID:Acute regulation of glucose transport in a monocyte-macrophage cell line: Glut-3 affinity for glucose is enhanced during the respiratory burst. 935 3


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