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 combination of tumour necrosis factor alpha (TNF alpha) and gamma-interferon induced transcription of class I HLA genes in chronic myelogenous leukaemia (CML) cell lines through the formation of a complex between nuclear proteins and the transcriptional enhancers associated with these genes. Although gamma-interferon or TNF-alpha stimulated expression of class I HLA antigens in the EM2 and K562 CML cell lines when used alone, the effect of the combination of TNF-alpha and gamma-interferon was greater than that observed with either agent alone. The induction of class I HLA expression by gamma-interferon and TNF-alpha was inhibited completely by the isoquinoline sulfonamide H7, an inhibitor of protein kinase C. We conclude that the enhancement of the gamma-interferon induced transcriptional activation of class I HLA gene expression by TNF-alpha involves a protein kinase C-dependent pathway.
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PMID:Activation of class I HLA expression by TNF-alpha and gamma-interferon is mediated through protein kinase C-dependent pathway in CML cell lines. 190 10

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 mechanism by which circulating monocytes are attracted to sites of bone remodeling is unknown. We now report that tumor necrosis factor-alpha (TNF-alpha), a potent osteotrophic cytokine, was stimulatory for expression of the monocyte chemoattractant JE gene in osteoblastic MC3T3-E1 cells. TNF-alpha stimulated this JE gene expression transcriptionally. The presence of JE gene product in conditioned medium of the cytokine-treated cells was evidenced by an immunoprecipitation assay with antiserum specific for JE/MCP-1. The stimulated JE gene expression was markedly inhibited by H-7, a potent inhibitor of protein kinase C. Phorbol 12-myristate 13-acetate induced the JE gene expression, and the cytokine-induced JE gene expression was down-regulated by the phorbol ester pretreatment. TNF-alpha induced expression of both early protooncogenes, c-fos and c-jun, in the cells. Antisense oligonucleotides to these oncogenes significantly inhibited the cytokine-induced monocyte chemotactic activity. Furthermore, curcumin, a specific inhibitor of c-jun/AP-1, markedly inhibited JE gene expression and monocyte chemotactic activity induced by the cytokine. These results suggest that TNF-alpha may contribute to the regulation of remodeling and inflammation of bone tissues through the JE gene product.
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PMID:Tumor necrosis factor-alpha induces expression of monocyte chemoattractant JE via fos and jun genes in clonal osteoblastic MC3T3-E1 cells. 848 42

Phospholipase A2 (PLA2) activity has been suggested to mediate some of the tumor necrosis factor (TNF) induced cellular responses including cytotoxicity. We evaluated the induction of both the 85-kDa cytosolic phospholipase A2 (cPLA2) and non-pancreatic group II PLA2 gene expression by TNF-alpha in a human bronchial epithelial cell line (BEAS 2B cell). TNF-alpha (20 ng/ml) induced a significantly increased release of prelabeled [3H]arachidonic acid (AA) following 4-24 h incubation. Calcium ionophore A23187 (10(-5) M) further increased the [3H]AA release from the TNF-alpha-treated cells. In vitro activity assay revealed that TNF-alpha increased the dithiothreitol (DTT)-resistant PLA2 activity which was blocked by the cPLA2 inhibitor AACOCF3. Treatment with TNF-alpha for 4-24 h increased the cPLA2 protein and mRNA levels which were blocked by the broad inhibitor of protein kinases staurosporine, the protein kinase C (PKC) inhibitor calphostin C, and to a lesser extent the calcium/calmodulin-dependent protein kinase inhibitor W-7. Reverse transcription and polymerase chain reaction amplification of the group II PLA2 mRNA showed that it is expressed in human lung but not in the bronchial epithelial cell line. TNF-alpha failed to induce the expression of group II PLA2 in the BEAS 2B cells. These results demonstrate that the cPLA2 gene expression is up-regulated by TNF-alpha and this effect may contribute to the TNF-alpha stimulated AA release in airway epithelial cells.
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PMID:Tumor necrosis factor-alpha induces the 85-kDa cytosolic phospholipase A2 gene expression in human bronchial epithelial cells. 861 31

Monocyte chemotactic protein-1 (MCP-1), a specific chemoattractant for monocytes, has been thought to play an important role in the recruitment and accumulation of monocytes within the glomerulus seen in glomerular diseases. This study examined the role of tumor necrosis factor (TNF)-alpha-mediated cellular signal transduction pathways on mesangial cell MCP-1 gene expression and monocyte migration. Incubation of mesangial cells with TNF-alpha stimulated MCP-1 mRNA expression in a dose- and time-dependent manner. Phorbol myristate acetate (PMA), a protein kinase C (PKC) activator, increased MCP-1 message by mesangial cells while depleting PKC decreased MCP-1 gene expression to control levels. Activation of PKC-depleted mesangial cells with PMA but not with TNF-alpha inhibited MCP-1 mRNA expression. Similarly, calphostin C, a PKC inhibitor, failed to inhibit TNF-alpha-induced MCP-1 expression. The incubation of mesangial cells with various protein tyrosine kinase inhibitors (PTK, e.g., herbimycin, tyrphostin, genistein) blocked TNF-alpha-induced MCP-1 mRNA message. Additional experiments examining the role of cAMP on MCP-1 expression indicated that the preincubation of mesangial cells with various cAMP generating substances (pertussis toxin, isoproterenol, dbcAMP) did not induce mesangial cell MCP-1 mRNA transcripts. However, the coincubation of mesangial cells with TNF-alpha and dbcAMP completely inhibited TNF-alpha-induced MCP-1 gene expression. Finally, TNF-alpha-activated mesangial cell media increased monocyte transmigration that could be blocked by neutralizing anti-MCP-1. These studies indicate that TNF-alpha facilitates monocyte transmigration into the glomerulus mediated by the increased expression of MCP-1 by mesangial cells. TNF-alpha-induced mesangial cell MCP-1 expression is regulated by signal transduction pathways involving PTK but not those dependent on PKC or cAMP.
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PMID:Role of tumor necrosis factor-alpha on mesangial cell MCP-1 expression and monocyte migration: mechanisms mediated by signal transduction. 879 1

Pulmonary surfactant has a potential role in modulating inflammation in normal and injured lungs. In lung injury, monocytes become activated and participate in lung inflammation. We therefore, investigated the proinflammatory functions of stimulated human blood monocytes after an overnight preincubation period with modified natural porcine surfactant (Curosurf) (500-1000 micrograms/mL). Monocytes were stimulated either with phorbol myristate acetate (PMA), bacterial extract OM-85, lipopolysaccharide (LPS), or Ca2+ ionophore A23187. The present study shows that Curosurf significantly inhibits: 1) the production of superoxide anions stimulated with OM-85 (1 mg/mL, 30 min), but not with PMA (100 ng/mL, 30 min); 2) the release of cyclooxygenase metabolites prostaglandin E2 and thromboxane B2 stimulated with OM-85 (1 mg/mL, overnight); 3) the release of lipoxygenase metabolite leukotriene C4 stimulated with A23187 (10 microM, 10 min); 4) the release of the cytokine TNF-alpha stimulated overnight with either OM-85 (1 mg/mL) or LPS (10 micrograms/mL)) in a dose-dependent fashion. In addition, Curosurf decreases the spontaneous adherence of monocytes to plastic culture wells in a dose-dependent fashion. Experiments performed with staurosporine, an inhibitor of protein kinase C (PKC) indicate that, in contrast with PMA, the production of superoxide anions stimulated by OM-85 is not related to PKC activation. Consequently, we propose that the mechanism involved in the suppressive effects of Curosurf is PKC-independent. In summary, the present study provides experimental evidence that favors the anti-inflammatory role of modified natural porcine surfactant (Curosurf) in human monocytes in vitro.
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PMID:Modified natural porcine surfactant inhibits superoxide anions and proinflammatory mediators released by resting and stimulated human monocytes. 897 99

The study of tumor promotion in rodent carcinogenesis using chemical tumor promoters has revealed various tumor promotion pathways, such as the 12-O-tetradecanoylphorbol-13-acetate (TPA) pathway mediated through activation of protein kinase C, and the okadaic acid pathway mediated through inhibition of protein phosphatases 1 and 2A (PP-1 and PP-2A). We previously demonstrated that application of TPA and okadaic acid induced tumor necrosis factor-alpha (TNF-alpha) gene expression in mouse skin, but that tautomycin, which is an inhibitor of PP-1 and PP-2A and not a tumor promoter on mouse skin, did not. Moreover, we found that TNF-alpha stimulated transformation of BALB/3T3 cells initiated with 3-methylcholanthrene 1,000 times stronger than did TPA (Cancer Res. 53, 1982-1985, 1993). This evidence demonstrates a link between the okadaic acid pathway and the endogenous tumor promotion pathway of TNF-alpha. Recently we presented the first evidence that tumor promotion in TNF-alpha(-/-) mice was significantly depressed compared with TNF-alpha(+/+) mice. Thus, in human carcinogenesis, we think that TNF-alpha and other inflammatory cytokines in preneoplastic lesion stimulate tumor promotion and progression of initiated cells as well as premalignant cells. The first part of this paper reports on this TNF-alpha tumor promotion pathway. In the second part, we report a promising screening method for cancer preventive agents, based on evidence that pretreatment with agents such as tamoxifen, sulindac, 1alpha, 25-(OH)2 vitamin D3, quercetin, caffeic acid phenethyl ester, and (-)-epigallocatechin gallate (EGCG) commonly inhibited TNF-alpha release from BALB/3T3 cells induced by okadaic acid. EGCG, the main constituent of Japanese green tea, and green tea itself are acknowledged cancer preventives in Japan, and this paper presents evidence of their effectiveness in both a high-risk group and the general population.
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PMID:A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea--a review. 1075 28

Signaling pathways associated with tumor necrosis factor (TNF)-alpha-induced intercellular adhesion molecule 1 (ICAM-1) surface and gene expression were investigated in well differentiated normal human bronchial epithelial (NHBE) cells in air-liquid interface primary culture. Cells were exposed to human recombinant TNF-alpha (hrTNF-alpha; 0.015 to 150 ng/ml [specific activity, 2.86 x 10(7) U/mg]). TNF-alpha enhanced ICAM-1 surface expression (measured by flow cytometry) and steady-state messenger RNA (mRNA) levels (assessed by Northern hybridization) in concentration- and time-dependent manners. TNF-alpha-induced ICAM-1 surface and gene expression were both blocked by the RNA polymerase II inhibitor actinomycin D (0.1 microg/ml), and surface expression was attenuated by a neutralizing monoclonal antibody directed against the TNF-alpha receptor p55 (TNF-RI). The intracellular signaling pathway leading to enhanced expression appeared to involve activation of a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC) because D609, a specific PC-PLC inhibitor, attenuated TNF-alpha-induced increases in production of diacyl-glycerol (DAG), a hydrolysis product of PC-PLC, and also attenuated TNF-alpha enhancement of ICAM-1 surface and gene expression. Because DAG formed by action of PC-PLC can activate protein kinase C (PKC), involvement of PKC was investigated. The specific PKC inhibitor calphostin C blocked both surface and gene expression of ICAM-1 in response to TNF-alpha in a concentration-dependent manner. Finally, TNF-alpha stimulated binding of p65 and/or c-rel complexes to the nuclear factor (NF)-kappaB consensus binding site found on the ICAM-1 promoter, and binding of these complexes was inhibited by D609. The results support the following pathway, whereby TNF-alpha enhances expression of ICAM-1 in NHBE cells: TNF-alpha --> TNF-RI --> PC-PLC --> DAG --> PKC --> (NF-kappaB?) --> ICAM-1 mRNA --> ICAM-1 surface expression.
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PMID:Effects of TNF-alpha on expression of ICAM-1 in human airway epithelial cells in vitro. Signaling pathways controlling surface and gene expression. 1083 65

Tumor necrosis factor-alpha (TNF-alpha) is implicated in muscle atrophy and weakness associated with a variety of chronic diseases. Recently, we reported that TNF-alpha directly induces muscle protein degradation in differentiated skeletal muscle myotubes, where it rapidly activates nuclear factor kappaB (NF-kappaB). We also have found that protein loss induced by TNF-alpha is NF-kappaB dependent. In the present study, we analyzed the signaling pathway by which TNF-alpha activates NF-kappaB in myotubes differentiated from C2C12 and rat primary myoblasts. We found that activation of NF-kappaB by TNF-alpha was blocked by rotenone or amytal, inhibitors of complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, an inhibitor of complex III, enhanced TNF-alpha activation of NK-kappaB. These results suggest a key role of mitochondria-derived reactive oxygen species (ROS) in mediating NF-kappaB activation in muscle. In addition, we found that TNF-alpha stimulated protein kinase C (PKC) activity. However, other signal transduction mediators including ceramide, Ca2+, phospholipase A2 (PLA2), and nitric oxide (NO) do not appear to be involved in the activation of NF-kappaB.
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PMID:Mitochondria mediate tumor necrosis factor-alpha/NF-kappaB signaling in skeletal muscle myotubes. 1122 36

Matrix metalloproteinases (MMPs) are the proteases involved in the degradation of the extracellular matrix. MMP-1 is thought to be one of the key enzymes in fibrolysis, a process closely related to tissue remodeling. In the present study, we investigated MMP-1 secretion from human pancreatic periacinar myofibroblasts in response to pro-inflammatory cytokines IL-1beta and TNF-alpha. We also attempted to clarify the intracellular signaling pathways mediating the cytokine-induced MMP-1 secretion. MMP-1 secretion was measured by an enzyme-linked immunosorbent assay. MMP-1 molecules were analyzed by Western blotting. MMP-1 mRNA expression was evaluated by Northern blotting. IL-1l and TNF-alpha stimulated the MMP-1 secretion in a dose- and time-dependent manner. Ninety percent of MMP-1 was secreted as inactive form (pro-MMP-1). The effects of IL-1beta and TNF-alpha were significantly inhibited by PD98059 MEK/ERK inhibitor). In contrast, SB203580 (p38 MAPK inhibitor), GF109203X (PKC inhibitor), and PDTC (NF-kappaB inhibitor) did not alter the MMP-1 secretion induced by IL-1beta and TNF-alpha. These effects were also observed at them RNA level. In conclusion, in human pancreatic periacinar myofibroblasts, MMP-1 secretion was regulated by the pro-inflammatory cytokines via the MEK/ERK cascade. Thus, human pancreatic periacinar myofibroblasts may play an important role in the remodeling of damaged pancreatic tissue in chronic pancreatitis via MMP-1 secretion.
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PMID:Pro-inflammatory cytokine-induced matrix metalloproteinase-1 (MMP-1) secretion in human pancreatic periacinar myofibroblasts. 1452 52


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