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)

HL60 and EL4 cells incubated with tumor necrosis factor-alpha (TNF-alpha) plus staurosporin, a potent inhibitor of protein kinases, showed at least 2-fold increased levels of nuclear factor-kappa B (NF-kappa B) activity compared with TNF-alpha alone both during rapid NF-kappa B activation from the cytosolic pool and protein synthesis-dependent NF-kappa B activation. NF-kappa B activation by phorbol 12-myristate 13-acetate (PMA) and interleukin-1 was inhibited by staurosporin. Staurosporin treatment hardly affected the TNF-alpha-induced increase in mRNA for the p51 subunit of NF-kappa B but interfered with any phorbol ester (PMA)-induced increase in p51 mRNA. Thus, induction of NF-kappa B and p51 mRNA by TNF-alpha was not mediated by a staurosporin-sensitive factor, but NF-kappa B activation by TNF-alpha was even reduced by action of a staurosporin-sensitive factor. Decreased levels of phosphorylation of TNF-R alpha (TNF receptor type alpha) after staurosporin-treatment correlated with increased induction of NF-kappa B by TNF-alpha. Staurosporin-treatment did not affect TNF-R levels. Although protein kinase C stimulation by PMA inhibited NF-kappa B activation by TNF-alpha, its action mechanism may be different from that of the staurosporin-sensitive factor. PMA induced disappearance of TNF-R alpha by shedding into the surrounding medium, with kinetics similar to those of its inhibition of NF-kappa B activation by TNF-alpha. Phosphorylation may not mediate receptor shedding, since PMA treatment did not detectably affect TNF-R alpha phosphorylation.
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PMID:Protein kinases negatively affect nuclear factor-kappa B activation by tumor necrosis factor-alpha at two different stages in promyelocytic HL60 cells. 173 Jul 37

The effect of the human rIL-1 alpha and rTNF-alpha on the binding of 125I-labeled epidermal growth factor ([125I]EGF) to its receptor (EGF-R) has been studied in human gingival fibroblasts (HuGi). Incubation of these cells with recombinant cytokines at 37 degrees C caused a rapid, dose-dependent decrease in their ability to subsequently bind subsaturating levels of [125I]EGF at 4 degrees C. Inhibition was evident at 5 min after addition of cytokines, reached a maximal level (60-70% reduction) after 15 to 30 min, and declined thereafter. Normal EGF binding was attained by 2 h. Half-maximal inhibition of EGF binding occurred at 10 pM IL-1 and 50 pM TNF. The two cytokines were not additive in their effect. Competition experiments at 4 degrees C showed that the cytokines did not interact directly with EGF-R; Scatchard analysis of binding of [125I]EGF to HuGi after treatment with IL-1 and TNF revealed an increase in EGF-R Kd from 0.75 nM to 2.9 nM with no change in receptor number. The effect of IL-1 and TNF on EGF-R was compared with that of the tumor-promotor PMA which is known to "transmodulate" EGF-R affinity by activating protein kinase C which then phosphorylates EGF-R. PMA caused a greater inhibition of EGF binding to HuGi (80 to 85% inhibition; ED50 = 500 pM), and recovery of binding was much slower. Importantly, in HuGi made deficient in protein kinase C by prolonged incubation with PMA, addition of fresh PMA no longer affected EGF binding, while the response to IL-1 and TNF was intact. Cytokine- but not PMA-mediated EGF-R transmodulation was partially reversed by treatment of the cells with millimolar concentrations of the kinase inhibitor amiloride. HuGi were incubated with H3 32PO4, stimulated with PMA or cytokines, and EGF-R were immunoprecipitated; IL-1 and TNF, like PMA, caused a 2- to 5-fold increase in receptor phosphorylation. We conclude that occupation of IL-1 and TNF-R activates a protein kinase, distinct from kinase C, for which EGF-R is a substrate.
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PMID:IL-1 and TNF transmodulate epidermal growth factor receptors by a protein kinase C-independent mechanism. 278 20

TNF is a potent activator of neutrophil granulocytes which acts via two cell surface receptors: the p55-TNF receptor (TNF-R55) and the p75-TNF receptor (TNF-R75). The extracellular region of the receptors can be released by proteolytic cleavage and form soluble TNF-binding proteins, TNF-R55-BP and TNF-R75-BP, respectively. The phorbol ester PMA, the chemotactic peptide FMLP, and TNF were all found to induce release of TNF-R55-BP and TNF-R75-BP from neutrophils in suspension in a time- and dose-dependent manner as measured by ELISA. Exposure of neutrophils to 10 ng/ml of PMA for 60 min resulted in release of 900 pg of TNF-R55-BP and 350 pg of TNF-R75-BP per 5 million cells, corresponding to approximately 4800 receptors per cell. In addition, adherence by itself of neutrophils to fibrinogen-coated culture plates and other surfaces resulted in a release of TNF-R55-BP of the same magnitude as seen in response of neutrophils in suspension to 1 nM TNF, whereas the release of TNF-R75-BP was less pronounced. The protein kinase C inhibitors staurosporin and calphostin C inhibited both the TNF-, PMA-, and adherence-induced release of soluble forms of TNFRs. Ab to the common beta-chain of the leukocyte integrins (CD18) did not affect adherence-induced TNF-R55-BP release, indicating that non-integrin-dependent mechanisms are involved in receptor cleavage. However, cross-linking of anti-CD18 Ab (IB4) with a Fab2 fragment resulted in a decrease of specific binding of 125I-TNF to neutrophils indicating that the leukocyte integrins can modulate TNFR expression on neutrophils. Thus, adherence to a biological surface, without additional stimuli, induces release of soluble TNFR form from neutrophils. TNFR expression can be modulated by protein kinase C as well as both leukocyte integrins and non-integrin-dependent adherence mechanisms.
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PMID:Adherence of neutrophils induces release of soluble tumor necrosis factor receptor forms. 790 2

The two tumor necrosis factor (TNF) receptors (TNF-R55 and TNF-R75) can release soluble TNF-binding proteins (TNF-R55-BP and TNF-R75-BP) by proteolytic cleavage. The proteolytic processing of the TNF receptors was investigated in monoblastic THP-1 and promyelocytic HL-60-10 leukemic cell lines. The release of soluble forms of both receptors was rapidly stimulated by staurosporine-sensitive protein kinase C activation by phorbol myristate acetate (PMA) and more slowly stimulated by TNF. No receptor release was seen below a temperature of 16 degrees C. NH4Cl (10 mmol/liter) and monensin (1 mumol/liter), known to increase intracellular pH, inhibited to some extent PMA- and TNF-induced release of both TNF-R55-BP and TNF-R75-BP. The inhibitory effect of monensin might be explained by a diminished translocation of newly synthesized receptor to the plasma membrane. The weak inhibitory effect of NH4Cl on PMA-induced release of soluble receptor forms could be due to effects on a pH-sensitive compartment. PMA-induced down-regulation of receptors was not dependent on acidity as it occurred also in the presence of monensin and NH4Cl when the release of TNF-BPs is partially blocked. Dibutyryl cAMP inhibited the PMA-induced release of TNF-R55-BP but not of TNF-R75-BP in both cell lines investigated. In addition, dibutyryl cAMP alone stimulated the release of both receptors but only in THP-1 cells. Our data show that the generation of soluble forms of both TNF receptors can be regulated by both PKC and PKA.
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PMID:Mechanisms involved in the processing of the p55 and the p75 tumor necrosis factor (TNF) receptors to soluble receptor forms. 794 29

Two separate tumor necrosis factor (TNF) receptors of approximately 55 kDa (TNF-R55) and 75 kDa (TNF-R75) have been identified. The role of protein kinase A activation by dibutyryl cAMP (dbcAMP) and of protein kinase C activation with phorbol myristate acetate (PMA) for transcriptional and posttranscriptional regulation of the two receptors was investigated in promyelocytic HL-60 cells. Incubation with dbcAMP or the adenylate cyclase agonist forskolin caused an increase in the level of TNF-R75 mRNA while TNF-R55 mRNA was unaffected. The half-life of transcripts for both TNF-R55 and TNF-R75 was unaffected as judged by disappearance of mRNA after inhibition of transcription with actinomycin D. Thus the transcription of the TNF-R75 gene seemed to be enhanced by activation of protein kinase A. This enhancement was not dependent on de novo protein synthesis. Incubation with PMA did not affect the mRNA level of any of the TNF receptors. Both TNF-R55 and TNF-R75 mRNA showed a prolonged half-life after incubation with the inhibitor of protein synthesis cycloheximide, indicating superinduction of the genes. Our results demonstrate that the two TNF receptors can be regulated differently at the transcriptional level and that both transcriptional and posttranscriptional regulation occurs.
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PMID:Independent transcriptional and posttranscriptional regulation of the two tumor necrosis factor receptors in promyelocytic HL-60 cells. 821 93

The expression and cytokine-mediated regulation of the two different receptors for tumor necrosis factor, TNF-R-75 and TNF-R-55, was investigated in human malignant epithelial cell lines. Here we show that cells treated with TNF-alpha up-regulate the TNF-R-75 mRNA and protein levels. No changes were seen regarding the level of TNF-R-55 transcripts. Phospholipase and protein kinase C inhibitors abrogated the signal transduction pathway of TNF-mediated TNF-R-75 mRNA up-regulation which proceeded in the absence of transcriptional activation. This process was also elicited by an agonistic antibody binding specifically to TNF-R-55. Ligand binding assays using specific inhibitory antibodies showed a marked shift in active binding sites from p55 to p75 without significant changes in the total binding for TNF-alpha after up-regulation of p75 TNF-R. This ligand-induced regulation of one of the corresponding receptors has so far only been detected in malignant epithelial cells and not in hematopoietic cell lines. In our search for a specific function we were able to show that p75 is the specific receptor for TNF-mediated up-regulation of transforming growth factor alpha mRNA, whereas p55 is the signal transducer for TNF-induced up-regulation of epidermal growth factor receptor mRNA. This is the first demonstration of an exclusive function of TNF-R-75 in cells of epithelial origin.
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PMID:Tumor necrosis factor (TNF) up-regulates the expression of p75 but not p55 TNF receptors, and both receptors mediate, independently of each other, up-regulation of transforming growth factor alpha and epidermal growth factor receptor mRNA. 838 14

Human peritoneal mesothelial cells (HPMC) respond to tumor necrosis factor alpha (TNF alpha) by releasing various cytokines that may activate the endothelium and induce recruitment of leukocytes during peristonitis. We characterized the receptors for TNF on HPMC to elucidate their functions in peritonitis. Scatchard analysis determined the presence of 70 x 10(3) TNF receptors/cell with a kDa of 0.44 nM. TNF receptor 1 (TNF-R1, p55) and TNF-R2 (p75) mRNA were demonstrated by reverse-transcriptase-PCR (RT-PCR). TNF-R1 protein was solely detected by flow cytometry (FCM). Interleukin-1 alpha (IL-1 alpha) induced down-regulation of TNF-R1. This was concomitant with accumulation of soluble TNF-R1 (sTNF-R1) detected by specific ELISA. LPS had a lower TNF-R1-shedding activity while TNF alpha did not induce shedding. The IL-1-induced-sTNF-R1-shedding was suppressed by the protein-kinase-A (PKA) inhibitor, H-8, or by H-7, the inhibitor of both PKC and PKA, but not by the specific PKC inhibitor GF. These experiments suggest a role for PKA in the IL-1-shedding signal. No change in TNF-R1 mRNA levels was observed after IL-1 alpha or TNF alpha stimulation while TNF-R2 (p75) mRNA basal levels transiently increased three to fivefold, reaching a peak after four hours followed by an accumulation of sTNF-R2 in the supernatant. Our data suggest that the main receptor expressed on HPMC is TNF-R1. Down-regulation and shedding of TNF-R1 induced by IL-1, and the transient expression of TNF-R2 induced by IL-1 and TNF, may regulate the responses to TNF by HPMC. These results may be important in understanding the inflammatory process of peritonitis were TNF plays a major role.
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PMID:TNF-receptors on human peritoneal mesothelial cells: regulation of receptor levels and shedding by IL-1 alpha and TNF alpha. 880 91

Tumor necrosis factor (TNF) may contribute to the pathogenesis of inflammatory airway disorders via the regulation of inflammatory and cellular immune responses. Shed cell surface TNF receptors can act as soluble TNF binding proteins and modulate TNF biological activity. We report that normal human airway epithelial cells, as well as two human airway epithelial cell lines, shed soluble type I TNF receptors (sTNF-RI) in a concentration-dependent fashion following protein kinase C (PKC) activation by PMA. Interleukin (IL)-1beta also induced concentration-dependent sTNF-RI shedding from NCI-H292 cells, which could be inhibited by the PKC inhibitor calphostin C. Since corticosteroids are commonly utilized as antiinflammatory agents in airway disorders, the effect of dexamethasone on sTNF-RI release was assessed. Dexamethasone inhibited constitutive, as well as PMA- and IL-1beta-mediated sTNF-RI release from NCI-H292 cells in a concentration-dependent fashion. Furthermore, dexamethasone increased while PMA decreased total cellular 55 kDa TNF-RI protein as detected by immunoblotting. These changes in total cellular 55kDa TNF-RI protein did not appear to be mediated at the mRNA level, as assessed by ribonuclease protection assays. This suggests that sTNF-RI shedding represents a mechanism by which airway epithelial cells can actively participate in local cytokine networks and modulate TNF-mediated inflammation. Furthermore, since corticosteroids inhibit sTNF-RI release and are known to downregulate TNF synthesis, this may represent a mechanism by which equilibrium between TNF ligand and soluble binding protein is maintained in the airway microenvironment.
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PMID:Protein kinase C, interleukin-1 beta, and corticosteroids regulate shedding of the type I, 55 kDa TNF receptor from human airway epithelial cells. 884 76

Within the past several years research on the interaction of cytokines and adhesion molecules with airway epithelium in diseases has allowed us to develop a better understanding of the disease process. The cytokine, TNF alpha and the adhesion molecule ICAM-1 are important mediators in the pathogenesis of airway diseases such as asthma, chronic bronchitis, and adult respiratory distress syndrome. Effects of TNF alpha on ICAM-1 surface expression was investigated in both primary cultures of normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cell line BEAS-2B. TNF alpha (0.015-150 ng/mL) significantly enhanced ICAM-1 surface expression (measured by flow cytometry) in a dose and time-dependent manner, with peak expression seen at 24 hours. This response was negated by heat inactivation of the TNF alpha prior to incubation. TNF alpha-induced ICAM-1 expression also was inhibited by pre- and coincubation of TNF alpha with 3 micrograms/mL soluble TNF-R1 or by the PKC inhibitor, Calphostin C (0.1 and 0.5 microM). The ROI scavengers, dimethylthiourea (4 mM), and dimethyl sulfoxide (0.001%), enhanced TNF alpha-induced ICAM-1 expression. Collectively, these results indicate that TNF alpha-induced ICAM-1 surface expression is a specific receptor-mediated response (TNF-R1), which is mediated by mechanisms dependent on PKC and intracellular reactive oxygen species.
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PMID:Tumor necrosis factor alpha (TNF alpha)-induced ICAM-1 surface expression in airway epithelial cells in vitro: possible signal transduction mechanisms. 890 9

Reactive oxygen intermediates (ROIs) are among the important mediators in the pathogenesis of lung diseases in which tumor necrosis factor (TNF) plays a pivotal role. However, the effects of ROIs on the TNF- TNF receptor system remain unclear. Effects of hydrogen peroxide on the shedding of soluble tumor necrosis factor receptor (sTNF-R) were investigated in a pulmonary epithelial cell line (A549) using enzyme-linked immunoassay. A549 cells spontaneously released type I sTNF-R (sTNF-RI) into the culture medium. Hydrogen peroxide accelerated the release of sTNF-RI from the A549 cells time- and dose- dependently. Stimulated release of sTNF-RI by hydrogen peroxide or phorbol myristate acetate (PMA) was inhibited by pretreatment with the intracellular hydroxyl radical scavengers dimethyl sulfoxide and dimethyl thiourea. A synthetic metalloproteinase inhibitor (KB-R8301) inhibited not only spontaneous release of sTNF-RI but also shedding enhanced by hydrogen peroxide and PMA. Preincubation with a protein kinase C inhibitor, calphostin C, downregulated the hydrogen peroxide- or PMA-induced shedding of sTNF-RI. Neither genistein, a tyrosine kinase inhibitor, nor H-89, a protein kinase A inhibitor, inhibited shedding of sTNF-RI by hydrogen peroxide and PMA. Although the surface expression of TNF-R assessed by 125I-TNF specific binding was decreased in the presence of hydrogen peroxide or PMA, TNF-RI mRNA transcript levels remained unchanged. These results show that hydrogen peroxide is involved in the activation of metalloproteinase and protein kinase C responsible for the shedding of sTNF-RI. Accordingly, ROIs may alter TNF action by enhanced shedding of sTNF-RI and reducing its surface receptor expression.
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PMID:Hydrogen peroxide enhances shedding of type I soluble tumor necrosis factor receptor from pulmonary epithelial cells. 987 Sep 25


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