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)

Vascular cell adhesion molecule-1 (VCAM-1) is expressed not only by cytokine-activated endothelium in the kidney, but also by nonvascular cells such as renal tubular epithelial cells (TEC) and mesangial cells (MC). VCAM-1 is upregulated in these cells by the cytokines TNF-alpha, IL-1, and IFN-gamma. We have examined herein the regulation of VCAM-1 expression in TEC and the role played by protein kinase C (PKC). Activation of PKC with phorbol myristate acetate (PMA) or mezerein upregulates VCAM-1 expression by TEC dose-dependently. Maximal stimulation occurs after 6 hr, and declines thereafter. Activation of the protein kinase A pathway with forskolin does not upregulate VCAM-1. The TNF-alpha- and PMA-stimulated VCAM-1 expression is inhibited by the PKC and PKA inhibitor staurosporine (STS). The TNF-alpha-stimulated VCAM-1 expression is also inhibited by the PKC-specific inhibitor calphostin C. Protein synthesis inhibition with cycloheximide (CHX) and blocking of transcription with actinomycin D (ACT D) also inhibits the TNF-alpha and PMA-stimulated upregulation of VCAM-1. The TNF-alpha induced increase in VCAM-1 mRNA levels is blocked with STS and ACT D, but is superinduced with CHX. Thus, the TNF-alpha stimulated renal tubular VCAM-1 expression may involve activation of PKC and is transcriptionally regulated.
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PMID:Regulation of cytokine-stimulated vascular cell adhesion molecule-1 expression in renal tubular epithelial cells. 767 55

The T cell surface molecules CD5 and CD28 have been shown to be receptors for accessory signals in T cell activation. We here demonstrate that in the absence of any other activating stimulus, simultaneous ligation of CD5 and CD28 by mAb induces polyclonal T cell activation. Immobilization of the anti-CD28 and anti-CD5 mAb was an essential requirement for T cell stimulation. This was done either through coating of the culture plates with goat anti-mouse Ig, or by coculture with mitomycin C-treated Fc gamma R-bearing P815 mouse mastocytoma cells. Most importantly, T cells could also be stimulated with B7, the natural ligand of CD28, and anti-CD5 presented on irradiated 3T6 mouse fibroblasts co-transfected with human Fc gamma RII and with B7. Neither immobilized mAb 9.3 (anti-CD28) nor any of four different anti-CD5 mAb were mitogenic as a sole stimulus. Immobilized mAb identifying CD4, CD7, or LFA-1 were not co-mitogenic with either mAb 9.3 or one of the anti-CD5 mAb. The T cell proliferation induced by cross-linking of CD5 and CD28 is IL-2-dependent, as was demonstrated by the cell-surface expression of the p55 chain of the IL-2R, the production of IL-2, and inhibition of the proliferative response by the anti-IL-2R mAb anti-Tac. CD5/CD28 ligation induced production of TNF-alpha, but not of IL-4, and did not induce modulation of the TCR/CD3 complex. Expression of IL-2R (p55) and of CD69 preferentially occurred on CD29-low naive cells, and indicated that about 50% of the cultured cells were activated. Cell proliferation was not increased by adding monocytes to the cultures and it was inhibited by PKC inhibitors (H7 and staurosporine) and by cyclosporine A. In conclusion, our data provide evidence for a pathway of Ag-independent T cell activation via CD5 and CD28, which preferentially stimulates native T cells.
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PMID:Simultaneous ligation of CD5 and CD28 on resting T lymphocytes induces T cell activation in the absence of T cell receptor/CD3 occupancy. 767 24

Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1, E-selectin) are endothelial surface molecules that play a role for leukocyte recruitment to sites of inflammation, e.g., during contact hypersensitivity. We studied the effects of sensitizing agents (2,4-dinitro-benzenesulfonic acid, metal salt haptens) and chemically related substances on endothelial adhesion molecule expression. Using flow cytometry and an enzyme-linked immunosorbent assay, NiCl2 and, to a lesser extent, CoCl2 were found to up-regulate ICAM-1, VCAM-1, and ELAM-1 expression on cultured human umbilical vein endothelium whereas the other substances tested showed no effects. Induction of adhesion molecules by NiCl2 required de novo mRNA and protein synthesis. Up-regulation could be blocked by kinase inhibitor H-7 but not staurosporine, suggesting involvement of phosphorylation events independent of protein kinase C activation. Concomitant application of NiCl2 and neutralizing antibodies to IL-1 did not block up-regulation by the hapten demonstrating that the latter did not act via an IL-1-dependent autocrine mechanism. Regarding ELAM-1 induction, pre-treatment for 24 h with NiCl2 produced hyporesponsiveness to IL-1 and TNF-alpha upon restimulation, suggesting that NiCl2 and these cytokines may partially share a common pathway of activation. In addition, analysis of cultured foreskin specimens revealed that NiCl2 may induce up-regulation of ELAM-1 on microvascular endothelium in vivo. Our data demonstrate that both Ni++ and Co++ to which simultaneous contact sensitivity is frequently observed have the ability to directly up-regulate endothelial adhesion molecules. This shared property may represent an adjuvant mechanism that promotes sensitization and elicitation events in contact hypersensitivity to these haptens.
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PMID:Nickel chloride and cobalt chloride, two common contact sensitizers, directly induce expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule (ELAM-1) by endothelial cells. 768 25

Receptor-mediated superoxide (O2-.)-generation in human peripheral neutrophils (HPPMN) is enhanced by various priming agents, such as granulocyte colony stimulating factor (G-CSF) and tumor necrosis factor (TNF-alpha). We previously reported that this enhancement occurred in parallel with the priming agent-induced increase in protein tyrosyl phosphorylation which is sensitive to tyrosine kinase (TK) inhibitors [Akimaru K. et al. Arch. Biochem. Biophys. 298:703, 1992]. We describe here that nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and aspirin, modulate the priming and tyrosine phosphorylation of HPPMN. The enhancement by TNF-alpha of formylmethionyl-leucyl-phenylalanine (FMLP)-induced O2-. generation was not inhibited by 5 microM azide, whereas that of FMLP-induced luminol chemiluminescence (LCL) was sensitive. Enhancement of FMLP-induced O2-. generation and LCL by priming agents was inhibited by both aspirin and indomethacin in a concentration dependent manner. This inhibition by the NSAIDs was much stronger than that for FMLP-induced O2-. generation without priming. The half-inhibition dose of indomethacin and aspirin were 50 microM and 1.5 mM, respectively. The priming-induced enhancement of tyrosyl phosphorylation of some neutrophil proteins, such as that of 108 and 115 kDa, was also inhibited by aspirin and indomethacin in a dose-dependent manner. However, dose dependent inhibition of the enhanced O2-. generation by the NSAIDs was not completely similar to that of enhanced tyrosyl phosphorylation. However, PKC-mediated O2-. generation, which has little sensitivity to TNF-alpha or G-CSF, was rather stimulated by the NSAIDs. These findings suggest that aspirin and indomethacin inhibit also the early steps of neutrophil activation as reflected by their ability to inhibit priming and the related tyrosyl phosphorylation of neutrophil proteins.
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PMID:Effect of indomethacin and aspirin on the TNF-alpha-induced priming and protein tyrosyl phosphorylation of human neutrophils. 768 97

Intracellular protein phosphorylation is thought to be the initial step in cell activation. Bacterial lipopolysaccharide (LPS) induces a special set of the protein phosphorylation in the murine peritoneal macrophages, including p65 (molecular mass of 65 kDa) which is a substrate of serine kinase and the most dominant phosphorylated cytosolic protein. This article deals with the relation between the LPS-induced protein phosphorylation in the murine peritoneal macrophages and their productions of IL-1 beta and TNF-alpha. LPS-induced p65 phosphorylation seems to be dependent on protein kinase C (PKC) and calmodulin (CaM), because it diminishes in the presence of inhibitors to PKC or CaM. Tyrosine kinase inhibitors do not affect the p65 phosphorylation. The PKC inhibitors also affect the mRNA expressions and the productions of active molecules of IL-1 beta and TNF-alpha. Though the CaM inhibitor inhibits the mRNA expression and the active molecule production of IL-1 beta, it does not affect those of TNF-alpha. These results suggest that LPS-induced p65 phosphorylation is closely related to PKC and CaM, and that IL-1 beta production depends on PKC and CaM, while the TNF-alpha production is not dependent on CaM. These findings indicate the existence of multiple pathways and different regulatory mechanisms for transduction of LPS signal in the macrophages. Furthermore, LPS-induced phosphorylation is not observed in endotoxin tolerant macrophages after re-stimulation with LPS, suggesting that the LPS-stimulus signal is blocked at a site in the signal transduction-pathway before the point of phosphorylation of proteins in the tolerant macrophages.
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PMID:Intracellular protein phosphorylation in murine peritoneal macrophages in response to bacterial lipopolysaccharide (LPS): effects of kinase-inhibitors and LPS-induced tolerance. 768 35

The transepithelial paracellular permeability of an epithelium formed by LLC-PK1 cells increases upon activation of protein kinase C (PKC) by the phorbol ester tumor promoter, TPA, or in response to the cytokine tumor necrosis factor-alpha (TNF). Until recently, however, we have not been able to inhibit the permeability effects of TPA or TNF using any of the currently available serine-threonine kinase inhibitors. In this study we report the treatment of epithelial cell sheets with the selective PKC inhibitor bisindolylmaleimide, GF109203X, completely prevents the TPA-induced but not the TNF-alpha induced increase in tight junction permeability. While PKC-alpha still translocates from the cytosol to the membrane of TPA-stimulated epithelial cells overall PKC activity in the membrane fraction is markedly reduced in the presence of GFX.
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PMID:The protein kinase C inhibitor, bisindolylmaleimide, inhibits the TPA-induced but not the TNF-induced increase in LLC-PK1 transepithelial permeability. 773 36

Tumor necrosis factor (TNF-alpha) stimulates a number of signal transduction pathways in which phospholipases produce lipid second messengers. However, the immediate molecular targets of these messengers, in particular those of ceramide and arachidonic acid (AA) and their role in TNF signaling are not well defined. In this study we investigated the relationship of ceramide and AA in regulating an atypical PKC isozyme, PKC zeta. U937 cells responding to TNF-alpha treatment with NF kappa B activation displayed enhanced phosphorylation of PKC zeta, which is already detectable 30 s after stimulation. [14C]ceramide specifically binds to and regulates kinase activity of PKC zeta in a biphasic manner. Binding studies indicate high and low affinity binding with bmax values of 60 and 600 nM and Kd values of 7.5 and 320 nM respectively. At ceramide concentrations as low as 0.5 nM an up to 4-fold increase in autophosphorylation is obtained, which, at concentrations > 60 nM, again declines to basal levels. Interestingly, AA competes for ceramide binding and inhibits basal and ceramide-stimulated PKC zeta kinase activity at < 100 nM. Metabolism of [14C]ceramide in cells is slow and is inhibited in the presence of equimolar concentrations of lyso-phosphatidylcholine. Based on the bifunctional modulation of PKC zeta by the lipid messengers ceramide and AA, a model of TNF signal pathways is suggested in which PKC zeta takes a central position, acting as a molecular switch between mitogenic and growth inhibitory signals of TNF-alpha.
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PMID:PKC zeta is a molecular switch in signal transduction of TNF-alpha, bifunctionally regulated by ceramide and arachidonic acid. 774 3

Taxol has been known to block cell division by stabilizing microtubules with promising anticancer activity. However, taxol has distinct cell cycle-independent effects. Recently, this novel drug has been shown to provide a second signal for murine macrophage activation to tumoricidal activity via L-arginine-dependent nitric oxide (NO) synthesis. To investigate the mechanism of taxol-induced NO synthesis, we evaluated the ability of protein kinase C (PKC) inhibitors such as staurosporine (STSN) or polymyxin B to block taxol-induced effects. Taxol alone had only a small effect, whereas taxol in combination with rIFN-gamma markedly increased NO synthesis in a dose-dependent manner. STSN and polymyxin B decreased NO synthesis, which had been induced by rIFN-gamma plus taxol. Furthermore, prolonged incubation of the cells with phorbol ester, which down-regulates PKC activity, abolished synergistic cooperative effect of taxol with rIFN-gamma on NO synthesis. Synergy between IFN-gamma and taxol was mainly dependent on taxol-induced TNF-alpha secretion because not only the increase of inducible NO synthase (iNOS) gene expression by rIFN-gamma plus taxol was associated with the increased expression of TNF-alpha gene but also taxol-induced NO production was decreased by the treatment of anti-murine TNF-alpha neutralizing Abs. STSN and polymyxin B potently inhibited taxol-induced TNF-alpha secretion and TNF-alpha gene expression as well as iNOS gene expression by rIFN-gamma plus taxol. However, rIFN-gamma plus TNF-alpha-induced NO synthesis was not blocked by STSN or polymyxin B. This result indicates that TNF-alpha-induced signaling for induction of NO synthesis is not dependent on PKC activation, and further suggests that the point at which TNF-alpha acts on the NO synthesis from rIFN-gamma-primed macrophages lies next to the point of PKC activation. In conclusion, the present results strongly suggest that the capacity of taxol to increase NO synthesis from rIFN-gamma-primed macrophages is the result of taxol-induced TNF-alpha secretion via the signal transduction pathway of PKC activation.
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PMID:Involvement of protein kinase C during taxol-induced activation of murine peritoneal macrophages. 775 87

1 alpha,25-Dihydroxyvitamin D3 [1 alpha,25(OH)2D3, calcitriol] has been shown to modulate the immune function of peripheral monocytes and peritoneal macrophages. However, its effect on alveolar macrophage (AM) cytokine secretion has not been reported. We therefore investigated the influence of calcitriol on tumor necrosis factor (TNF-alpha) production by murine AMs and attempted to elucidate changes in the signal transduction system involved in such effects. Calcitriol significantly enhanced TNF-alpha secretion by AM stimulated with either lipopolysaccharide (LPS; 10 micrograms/ml; p < 0.005) or phorbol 12-myristate 13-acetate (PMA; 100 ng/ml; p < 0.05) at low doses (between 10(-11) and 10(-9) M). However the protein kinase C (PKC) inhibitor, H7 (10 microM), and the Ca2+/calmodulin inhibitor, W7 (25 microM), reversed such calcitriol effects. Calcitriol increased the total PKC activity of AMs. These findings indicate that calcitriol enhances both LPS- and PMA-stimulated TNF-alpha secretion through PKC- or Ca2+/calmodulin-dependent pathways.
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PMID:Stimulatory effect of 1 alpha,25-dihydroxyvitamin D3 on mouse alveolar macrophage tumor necrosis factor-alpha production in vitro: involvement of protein kinase C and Ca2+/calmodulin-dependent kinase. 778 16

A critical role of tumor necrosis factor (TNF)-alpha in irritant contact dermatitis and in the challenge phase of allergic contact dermatitis has recently been demonstrated in vivo. As in situ hybridization studies have indicated that keratinocytes were the cellular source of TNF-alpha in these reactions, we studied the mechanisms of TNF-alpha mRNA induction in keratinocytes by agents that induce contact dermatitis. Murine la-/CD3- epidermal cells were stimulated with phorbol myristate acetate (PMA), dimethylsulfoxide (DMSO), sodium dodecyl sulfate (SDS) and NiSO4, all of which up-regulated epidermal cell TNF-alpha mRNA production. In contrast, trinitrobenzenesulfonic acid and trinitrochlorobenzene did not significantly up-regulate TNF-alpha mRNA. These results were confirmed with murine keratinocyte cell lines. In keratinocytes transfected with a chloramphenicol acetyltransferase construct containing the -1059 to +138 base pair TNF-alpha promoter, increased promoter activity was observed upon stimulation with PMA and DMSO. In addition, PMA stimulation did not affect the stability of TNF-alpha mRNA. The PMA- but also the DMSO- and SDS- induced up-regulation of TNF-alpha mRNA was abolished by an inhibitor of protein kinase C (PKC). In contrast, NiSO4 up-regulated TNF-alpha mRNA by a PKC-independent mechanism, did not increase TNF-alpha promoter activity, but markedly increased the stability of the TNF-alpha mRNA. Co-stimulation with PMA and NiSO4 induced a marked increase in TNF-alpha mRNA over that obtained with each agent alone. Thus, whereas PKC-dependent irritants act by up-regulating TNF-alpha promoter activity, nickel acts via post-transcriptional regulation. Our results also establish that some irritants and irritant sensitizers directly induce TNF-alpha in keratinocytes without intermediate Langerhans cell-derived signals.
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PMID:Nickel and skin irritants up-regulate tumor necrosis factor-alpha mRNA in keratinocytes by different but potentially synergistic mechanisms. 779 16


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