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)

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that has a large number of immunologic and nonimmunologic functions. We have described that IFN-gamma could activate muscarinic cholinergic receptors (mAchR) of rat intestine, stimulating ileal motility. We also observed that mAchR activation induced inhibition of cAMP levels and stimulation of cGMP formation. The objectives of our work were to clarify the signal transduction pathways involved in regulation of ileal motility through mAchR activation by IFN-gamma. Our results demonstrate that this cytokine produces an ileal cholinergic response through tyrosine kinase activity. The activation of tyrosine kinase mediates ileal contractility, phosphoinositide hydrolysis by phospholipase C, nitric oxide synthase via protein kinase C, and cGMP synthesis. The increment in ileal motility is probably due to hyperproduction of prostaglandin E2 (PGE2) by ileal tissue. This prostanoid is an important mediator because it stimulates ileal motility. We conclude that IFN-gamma not only immunomodulates the gut microenvironment but also exerts a local nonimmunologic regulation on intestinal motility.
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PMID:Tyrosine kinase regulatory action on ileal muscarinic effects of IFN-gamma. 1033 89

Interferon-gamma is a potent inducer of growth arrest and squamous differentiation of human epidermal keratinocytes in vitro. In order to understand the proximate events regulating interferon-gamma action we studied the relationship between interferon-gamma-mediated induction of a cytoplasmic guanylate-binding protein and the expression of growth and differentiation marker genes in normal and transformed keratinocytes. Induction of guanylate-binding protein mRNA by interferon-gamma was detectable at 4 h, was transcription dependent, and preceded changes in the expression of markers of growth arrest (E2F-1 mRNA downregulation) and differentiation (SQ37 mRNA induction). The Ec50 value for guanylate-binding protein induction (4 units interferon-gamma per ml) was lower than previously reported for SQ37 (40 units interferon-gamma per ml). Guanylate-binding protein mRNA appeared to be only moderately downregulated by modulators of the squamous phenotype such as retinoic acid and transforming growth factor-beta1. In addition, mRNA levels of E2F-1 or SQ37 were not altered in several squamous carcinoma cell lines treated with interferon-gamma. In contrast, guanylate-binding protein mRNA was highly induced in all these cell lines following interferon-gamma treatment. Further analysis of the signal transduction pathway mediating interferon-gamma responses using protein kinase inhibitors indicated that guanylate-binding protein induction in normal human epidermal keratinocyte cells was most likely protein kinase C independent. Our data suggest that more than one postreceptor interferon-gamma signaling pathway exists in keratinocytes and that at least one of these pathways is defective in squamous carcinoma cells. Furthermore, our data demonstrated that the failure of the squamous carcinoma cells to undergo interferon-gamma-induced growth arrest and differentiation is not due to an inherent defect in interferon-gamma receptor activation, but most likely is due to a defect in a non-guanylate-binding protein-dependent signaling pathway.
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PMID:Regulation of guanylate-binding protein expression in interferon-gamma-treated human epidermal keratinocytes and squamous cell carcinoma cells. 1038 48

Interferon-gamma (IFN-gamma) induced intercellular adhesion molecule-1 (ICAM-1) expression in human NCI-H292 epithelial cells, as shown by enzyme-linked immunosorbent assay and immunofluorescence staining. The enhanced ICAM-1 expression resulted in increased adhesion of U937 cells to NCI-H292 cells. Tyrosine kinase inhibitors (genistein or herbimycin), Src family inhibitor (PP2), or a phosphatidylinositol-phospholipase C inhibitor (U73122) attenuated the IFN-gamma-induced ICAM-1 expression. Protein kinase C (PKC) inhibitors (staurosporine or Ro 31-8220) also inhibited IFN-gamma-induced response. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a PKC activator, stimulated ICAM-1 expression; this effect was inhibited by tyrosine kinase or Src inhibitor. ICAM-1 promoter activity was enhanced by IFN-gamma and TPA in cells transfected with pIC339-Luc, containing the downstream NF-kappaB and gamma-activated site (GAS) sites, but not in cells transfected with GAS-deletion mutant, pIC135 (DeltaAP2). Electrophoretic gel mobility shift assay demonstrated that GAS-binding complexes in IFN-gamma-stimulated cells contained STAT1alpha. The IFN-gamma-induced ICAM-1 promoter activity was inhibited by tyrosine kinase inhibitors, a phosphatidylinositol-phospholipase C inhibitor, or PKC inhibitors, and the TPA-induced ICAM-1 promoter activity was also inhibited by tyrosine kinase inhibitors. Cotransfection with a PLC-gamma2 mutant inhibited IFN-gamma- but not TPA-induced ICAM-1 promoter activity. However, cotransfection with dominant negative mutants of PKCalpha or c-Src inhibited both IFN-gamma- and TPA-induced ICAM-1 promoter activity. The ICAM-1 promoter activity was stimulated by cotransfection with wild type PLC-gamma2, PKCalpha, c-Src, JAK1, or STAT1. An immunocomplex kinase assay showed that both IFN-gamma and TPA activated c-Src and Lyn activities and that these effects were inhibited by staurosporine and herbimycin. Thus, in NCI-H292 epithelial cells, IFN-gamma activates PLC-gamma2 via an upstream tyrosine kinase to induce activation of PKC-alpha and c-Src or Lyn, resulting in activation of STAT1alpha, and GAS in the ICAM-1 promoter, followed by initiation of ICAM-1 expression and monocyte adhesion.
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PMID:Interferon-gamma-induced epithelial ICAM-1 expression and monocyte adhesion. Involvement of protein kinase C-dependent c-Src tyrosine kinase activation pathway. 1175 11

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that modulates the immune function, cell proliferation, apoptosis, macrophage activation, and numerous other cellular responses. These biological actions of IFN-gamma are characterized by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanisms through which the cytokine suppresses gene transcription remain largely unclear. We show here for the first time that exposure of macrophages to IFN-gamma leads to a dramatic induction in the expression of the inducible cAMP early repressor (ICER), a potent inhibitor of gene transcription. In addition, a synergistic action of IFN-gamma and calcium in the activation of ICER expression was identified. The IFN-gamma-mediated activation of ICER expression was not blocked by H89, bisindoylmaleimide, SB202190, PD98059, W7, and AG490, which inhibit protein kinase A, protein kinase C, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, calcium-calmodulin-dependent protein kinase, and Janus kinase-2, respectively. In contrast, apigenin, a selective casein kinase 2 (CK2) inhibitor, was found to inhibit response. Consistent with this finding, IFN-gamma stimulated CK2 activity and the level of phosphorylated cAMP response element-binding protein, which is known to induce ICER gene transcription, and this response was inhibited in the presence of apigenin. These studies, therefore, identify a previously uncharacterized pathway, involving the IFN-gamma-mediated stimulation of CK2 activity, activation of cAMP response element-binding protein, and increased production of ICER, which may then play an important role in the inhibition of macrophage gene transcription by this cytokine.
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PMID:Interferon-gamma stimulates the expression of the inducible cAMP early repressor in macrophages through the activation of casein kinase 2. A potentially novel pathway for interferon-gamma-mediated inhibition of gene transcription. 1260 74

Interferon-gamma (IFN-gamma) is a major effector cytokine of the immune system with an expression pattern strictly restricted to cells of the lymphoid lineage. Several years ago, we reported that, during early pregnancy, the trophectoderm of the pig blastocyst, which represents a monolayer of polarized epithelial cells secretes high amount of IFN-gamma in a transient and developmentally regulated manner. In an effort to study the molecular basis of this atypical IFN-gamma gene expression, a pig trophectoderm cell line, TBA B4-3, was established in our laboratory. These cells developed a polarized phenotype with high transepithelial electrical resistance (TER) when grown on a microporous membrane. We found that treatment of polarized TBA B4-3 cells with the strong PKC agonist PMA induced, 3-4 days later, a transient IFN-gamma mRNA expression and vectorial IFN-gamma protein secretion. In order to better understand IFN-gamma gene regulation in TBA B4-3 cells, we examined in this system the effect of several drugs and factors known to affect the inducibility of this cytokine in T lymphocytes, the main source of IFN-gamma in the immunocompetent animal. We found that cyclosporine A (CsA) treatment of TBA B4-3 cells induces a partial inhibition of IFN-gamma secretion, thus indicating a minor role for the calcineurin signaling pathway in IFN-gamma expression. In addition, we found that although PMA alone can induce IFN-gamma secretion, the calcium ionophore A23187 synergizes with PMA for induction. We also analyzed by Southern blot the methylation status of a CpG dinucleotide in the 5' flanking region of IFN-gamma promoter and found that it was unmethylated in TBA B4-3 cells and in several pig epithelial cell lines that do not express IFN-gamma thus indicating the absence of correlation between demethylation and the ability to express IFN-gamma. Taken together, these results indicate that the mechanisms involved in IFN-gamma induction in TBA B4-3 cells are atypical compared to those presently known to operate in the T cell lineage.
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PMID:Atypical mechanisms regulate the PMA-induced expression of IFN-gamma in a porcine trophectoderm cell line. 1273 16

Microglial activation by amyloid beta-protein in senile plaques contributes to neurodegeneration in Alzheimer disease. In BV-2 microglial cells, amyloid beta-protein 1-40 (Abeta 1-40) elicited a dose-dependent increase (3-4 fold) of Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP), two protein kinase C substrates implicated in membrane-cytoskeletal alterations underlying microglial adhesion, migration, secretion, and phagocytosis. Neither MARCKS nor MRP was induced by the amyloid fragment Abeta 25-35, although both Abeta 1-40 and Abeta 25-35 caused extensive aggregation of BV-2 cells. Interferon-gamma synergistically enhanced the induction by Abeta 1-40 of inducible nitric oxide synthase, but not MARCKS or MRP. Our results suggest that MARCKS and MRP may play important roles in microglia activated by amyloid peptides.
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PMID:Induction of protein kinase C substrates, Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP), by amyloid beta-protein in mouse BV-2 microglial cells. 1286 29

Interferon-gamma (IFN-gamma) and interleukin-1 (IL-1) play an important role in the modulation of acute and chronic airway inflammation. Both IFN-gamma and IL-1 are known to increase the release of arachidonic acid (AA) from airway epithelial cells, suggesting that AA metabolites may mediate the cytokine-induced inflammation. This study was designed to examine the direct effect of IFN-gamma and IL-alpha on the phosphorylation of 85-kDa cytosolic phospholipase A(2) (cPLA(2)) and AA release in primary normal human bronchial epithelial (NHBE) cells. Treatment with IFN-gamma and IL-1alpha for 15 min induced a rapid increase of AA release from NHBE cells, which was blocked by the cPLA(2) inhibitor MAFP (p<0.05) but not by the sPLA(2) inhibitor LY311727 or iPLA(2) inhibitor HELSS. Immunoprecipitation and Western blot analysis showed that both IFN-gamma and IL-1alpha induced a rapid phosphorylation of cPLA(2). The IFN-gamma and IL-1alpha-induced cPLA(2) phosphorylation and AA release in the NHBE cells were inhibited by the p38 MAP kinase (MAPK) inhibitor SB203580, p42/44 MAPK inhibitor PD98059 and protein kinase C (PKC) inhibitor bisindolylmaleimide I. These results demonstrate the involvement of p38 and p42/44 MAPKs as well as PKC in the IFN-gamma and IL-1alpha-induced cPLA(2) phosphorylation and AA release in human airway epithelial cells.
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PMID:Involvement of p38 and p42/44 MAP kinases and protein kinase C in the interferon-gamma and interleukin-1alpha-induced phosphorylation of 85-kDa cytosolic phospholipase A(2) in primary human bronchial epithelial cells. 1468 81

Interferon-gamma (IFN-gamma) exerts an pleiotropic effect in mesangial cells in inflammatory glomerular diseases. The biologic effect of IFN-gamma is mediated by STAT1alpha. The precise mechanism by which IFN-gamma stimulates the transcriptional activity of STAT1alpha is poorly understood. I investigated the role of protein kinase C (PKC) epsilon in regulating the transcriptional activation of STAT1alpha in mesangial cells. IFN-gamma increased PKCepsilon activity in a time-dependent manner with a concomitant increase in STAT1alpha transcriptional activity. Expression of constitutively active PKCepsilon mimicked the effect of IFN-gamma on STAT1alpha-dependent transcription. Expression of dominant negative PKCepsilon inhibited IFN-gamma-induced STAT1alpha-dependent transcription. Ly294002, a pharmacological inhibitor of phosphatidylinositol (PI) 3-kinase, blocked IFN-gamma-induced PKCepsilon activity and resulted in inhibition of STAT1alpha transcriptional activity but had no effect on STAT1alpha tyrosine phosphorylation and STAT1alpha-DNA complex formation. A PKC inhibitor, H7, also had no effect on STAT1alpha tyrosine phosphorylation and DNA binding. However, Ly294002 and H7 blocked IFN-gamma-induced serine phosphorylation of STAT1alpha. These data indicate that PI 3 kinase-dependent PKCepsilon regulates STAT1alpha transcriptional activity in the absence of any effect on its DNA binding capability. In addition to activating PKCepsilon, IFN-gamma increased MAPK activity, resulting in transcriptional activation of Elk-1, a nuclear target of MAPK. Ly294002 or a dominant negative PI 3-kinase significantly blocked IFN-gamma-induced MAPK activity. On the other hand, ectopic expression of constitutively active PKCepsilon significantly increased MAPK activity. IFN-gamma-stimulated MAPK phosphorylated STAT1alpha in vitro. Inhibition of MAPK activity blocked IFN-gamma-induced serine phosphorylation of STAT1alpha; but its tyrosine phosphorylation and DNA binding were partially inhibited. Finally, expression of dominant negative MAPK significantly inhibited IFN-gamma-induced STAT1alpha-dependent transcription. These data provide the first evidence that IFN-gamma stimulates PKCepsilon in a PI 3-kinase-sensitive manner to activate MAPK, which regulates STAT1alpha transcriptional activity.
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PMID:A linear signal transduction pathway involving phosphatidylinositol 3-kinase, protein kinase Cepsilon, and MAPK in mesangial cells regulates interferon-gamma-induced STAT1alpha transcriptional activation. 1508 10

Glucose-6-phosphate dehydrogenase (G6PD) supports cellular antioxidant pathways. G6PD deficiency is associated with malaria protection but was shown to worsen the clinical course to injury. This study tested whether G6PD deficiency manifests in altered cytokine responses using peritoneal macrophages from a G6PD-deficient mouse model with a degree of defect similar to the common type A(-) human G6PD deficiency. Lipopolysaccharide (LPS)-induced interleukin (IL)-10 and IL-12 production was doubled in G6PD-deficient macrophages compared with wild-type (WT). Protein kinase C (PKC) activation by phorbol-ester prior to LPS resulted in a fivefold greater IL-10 production in G6PD-deficient macrophages compared with WT. Interferon-gamma treatment prior to LPS augmented IL-12 production in G6PD-deficient and WT macrophages and partially inhibited IL-10 production by G6PD-deficient macrophages. The antioxidants (N-acetyl-L-cysteine and glutathione ethyl-ester) blunted IL-10 and IL-12 production, indicating a role for oxidative stress in the observed response differences between deficient and WT macrophages. LPS-induced activation of nuclear factor-kappaB, cyclic adenosine monophosphate response element-binding protein, and specificity protein 3 was augmented in G6PD-deficient cells compared with WT. The PKCdelta inhibitor Rottlerin inhibited IL-10 and IL-12 production at different 50% effective-dose concentrations between deficient and WT macrophages, indicating elevated PKCdelta activity in deficient cells. This study reveals that activated G6PD-deficient macrophages display an augmented production of cytokines with a prominent impact on IL-10 production. The altered cytokine responses are associated with augmented activation of redox-dependent transcription factors and PKCdelta. Alterations in signaling pathways and associated changes in cytokine production may play a role in modulating the inflammatory responses following bacterial or malarial infections in G6PD deficiency.
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PMID:Augmented IL-10 production and redox-dependent signaling pathways in glucose-6-phosphate dehydrogenase-deficient mouse peritoneal macrophages. 1581 8

Monocyte chemotactic protein-1 (MCP-1) recruits activated phagocytes to the site of tissue injury. Interferon-gamma (IFN-gamma) present in the microenvironment of glomerulus acts on mesangial cells to induce local production of MCP-1. The mechanism by which IFN-gamma stimulates expression of MCP-1 is not clear. We therefore examined the role of PI 3 kinase signaling in regulating the IFN-gamma-induced MCP-1 expression in mesangial cells. Blocking PI 3 kinase activity with Ly294002 attenuated IFN-gamma-induced MCP-1 protein and mRNA expression. IFN-gamma increased Akt kinase activity in a PI 3 kinase-dependent manner. Expression of dominant negative Akt kinase inhibited serine phosphorylation of STAT1alpha, without any effect on its tyrosine phosphorylation, and decreased IFN-gamma-induced expression of MCP-1. These data for the first time indicate a role for PI 3 kinase-dependent Akt kinase in MCP-1 expression. We have recently shown that along with Akt, PKCepsilon is a downstream target of PI 3 kinase in IFN-gamma signaling. Similar to dominant negative Akt kinase, dominant negative PKCepsilon also inhibited serine phosphorylation of STAT1alpha without any effect on tyrosine phosphorylation. Dominant negative PKCepsilon also abrogated MAPK activity, resulting in decrease in IFN-gamma-induced MCP-1 expression. Furthermore, Akt and PKCepsilon are present together in a signaling complex. IFN-gamma had no effect on this complex formation, but did increase PKCepsilon-associated Akt kinase activity. PKCepsilon did not regulate IFN-gamma-induced Akt kinase. Finally, expression of dominant negative Akt kinase blocked IFN-gamma-stimulated MAPK activation. These data provide the first evidence that PI 3 kinase-dependent Akt and PKCepsilon activation independently regulate MAPK activity and serine phosphorylation of STAT1alpha to increase expression of MCP-1.
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PMID:PI 3 kinase-dependent Akt kinase and PKCepsilon independently regulate interferon-gamma-induced STAT1alpha serine phosphorylation to induce monocyte chemotactic protein-1 expression. 1615 72


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