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) induces HLA-DR and -DQ molecules and causes an accumulation of transcripts in HL-60 cells. Experiments were, therefore, designed to investigate the intracellular signaling molecules regulating the appearance of HLA class II molecules. The expression of HLA class II (DR and DQ) molecules induced by IFN-gamma was blocked by a calmodulin antagonist, W7, but not by a protein kinase C inhibitor, H7. Furthermore, a direct activator of protein kinase C, phorbol 12-myristate 13-acetate, was unable to induce HLA class II (DR) molecule expression. These results suggest that IFN-gamma induces HLA class II molecules on HL-60 cells by way of a calcium-calmodulin pathway and not by way of a protein kinase C pathway. Calmodulin is activated by a transient rise in the cytosolic free calcium. In fact, IFN-gamma evoked a calcium influx into HL-60 cells, whereas depletion of Ca2+ from culture medium resulted in a failure of IFN-gamma to induce DR expression. Furthermore, the calcium ionophore A23187 by itself induced DR molecule expression. These results suggest that IFN-gamma stimulates calcium influx by a so-called receptor-mediated calcium channel and activates the calmodulin branch of the calcium messenger system, resulting in the induction of DR molecules on the surface of HL-60 cells.
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PMID:Calcium influx and the Ca2+-calmodulin complex are involved in interferon-gamma-induced expression of HLA class II molecules on HL-60 cells. 296 98

The biochemical events leading to enhanced membrane expression of HLA-DR and CR3 by human peripheral blood monocytes (MO) following exposure to bacterial lipopolysaccharide (LPS) were examined. In a previous study we demonstrated that an increase in intracellular calcium was necessary, but not sufficient, for MO to increase membrane expression of both antigens within 1 hr of addition of LPS. The present study was initiated to examine the other biochemical requirements which lead to the MO response to LPS. Enhanced expression of both antigens following addition of LPS was dependent on microfilament function, but independent of microtubule function and of protein synthesis. Inhibition of formation of cyclooxygenase or lipoxygenase metabolites of arachidonic acid had no effect on HLA-DR or CR3 modulation by LPS. A role for phosphatidylinositol metabolism was suggested by the inhibition of the MO response to LPS by dibutyryl cAMP and theophylline and by the enhanced expression of both antigens following addition of phorbol diesters. However, H-7, a putative inhibitor of protein kinase C, did not alter the MO response to LPS or phorbol diesters. These results suggest that LPS enhances expression of HLA-DR and CR3 by inducing redistribution of these antigens from an intracellular pool. The data also support a role for the generation of hydrolysis products of phosphatidylinositol, leading to calcium redistribution and activation of protein kinase C or other kinases, in the MO response to LPS.
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PMID:Biochemical basis of HLA-DR and CR3 modulation on human peripheral blood monocytes by lipopolysaccharide. 303 40

Interferon-gamma (IFN-gamma) regulates a variety of biological functions and is the principal lymphokine known to activate macrophages. In studies of the molecular mechanisms by which these cells are regulated by IFN-gamma, the transcriptional activation of an IFN-gamma-inducible gene, gamma.1, in human macrophage-like cell lines was examined. Transcription of this gene is rapidly induced by 0.1-1 unit of IFN-gamma. In addition, gamma.1 transcription is efficiently induced by phorbol 12-myristate 13-acetate, which is known to activate protein kinase C (PKC). Both stimulators of gamma.1 transcription induce the translocation of PKC from the cytosol of a membrane fraction. Two selective inhibitors of PKC, H7 and sphingosine, suppressed not only the induction of gamma.1 mRNA but transcription of HLA-DR by IFN-gamma as well. These findings establish that PKC plays a significant role in the signal transduction pathway leading to transcriptional activation of some IFN-gamma-regulated genes of cells of the mononuclear phagocyte lineage.
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PMID:Interferon-gamma-induced transcriptional activation is mediated by protein kinase C. 313 57

Internalisation of CD4 is a well-known phenomenon. It occurs in the presence of phorbol myristate acetate (PMA), TPA or gangliosides and is usually completed within 30 min. Here, we describe an internalisation of CD4 molecules induced by low concentrations of high molecular weight dextran sulfate (M(r) 500 kDa) which differs from the classical mode in several ways. Internalisation is demonstrated by flow cytometry after simultaneous and consecutive staining of extracellular and internalised CD4 molecules and by visualisation by electron micrographs. A simple blockage of antibody binding sites on the CD4 molecule (epitope masking) by DS500, as widely believed, is definitely not responsible for the observed effects. DS500-mediated internalisation is a slow and energy-dependent process, where CD4 but not CD 2, 3, 8, 16, 56 and HLA-DR molecules are involved. The reaction reveals a characteristic time and concentration dependency. It does not require activation of protein kinase C (PKC) and cannot be inhibited by cytochalasin D. These results provide some more insight in the behavior of CD4 on lymphoid cell surfaces in response to high molecular weight polyanions such as dextran sulfate.
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PMID:Dextran sulphate induces a PKC and actin independent internalisation of CD4. 782 23

The human leukemic cell line NB4 was derived from a patient with acute promyelocytic leukemia and is characterized by a specific 15;17 chromosomal translocation. We analyzed the response of NB4 and HL-60 cells to the biomodulators all-transretinoic acid (ATRA), vitamin D3 (Vit D3) and the protein kinase C agonists bryostatin 1 (Bryo 1) and phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). HL-60 cells were used for comparison being arrested at the myeloblastic-promyelocytic stage, but lacking the t(15;17) abnormality. In most experiments Vit D3 was only weakly or not at all effective. The other three reagents effectively slowed or stopped the proliferation of the cells in suspension. Associated with this proliferation arrest was the cell differentiation along the myeloid cell lineages: ATRA modulated morphological features indicative of granulocytic differentiation; Bryo 1 and TPA caused also distinct morphological changes. The inducers up-regulated the expression of CD11b (without changing the surface expression of other markers, e.g. CD13, CD14, CD15, CD33, CD68, HLA-DR) and completely down-regulated the originally strong expression of myeloperoxidase and c-myc at the mRNA level. Thus, ATRA- or protein kinase C activator-induced differentiation involved changes associated with maturational processes. Induction of terminal differentiation of leukemic cells by physiological or pharmacological modulators may be able to control the growth of the malignant cells and has therapeutic implications.
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PMID:Modulation of gene expression in the acute promyelocytic leukemia cell line NB4. 790 56

MHC-class-II-positive T cells are found in tissues involved in autoimmune disorders. Stimulation of class II molecules by monoclonal antibodies (mAbs) or bacterial superantigens induces protein tyrosine phosphorylation through activation of protein tyrosine kinases in T cells, and class II signals modulate several T cell responses. Here, we studied further the role of class II molecules in the regulation of T cell growth. Costimulation of class II molecules by immobilized HLA-DR mAb significantly enhanced interleukin (IL)-2-supported T cell growth of the majority of CD4+, CD45RAlow, ROhigh T cell lines tested. Only one of three CD4+, CD45RAhigh, ROhigh T cells responded to class II costimulation. There was no correlation between T cell responsiveness to class II and the cytokine production profile of the T cell in question. Thus, T cell lines producing interferon (IFN)-gamma but not IL-4 (TH1-like) as well as T cells producing both cytokines (THO-like) responded to class II mAb. The costimulatory effect was not restricted to IL-2-driven T cell growth, since TCR/CD3-induced T cell activation was also enhanced by HLA-DR mAb. Moreover, class II costimulation potentiated CD28-mAb-induced T cell sensitivity to protein kinase C activation by phorbol 12-myristate 13-acetate. In conclusion, class II costimulation enhances T cell activation through the TCR/CD3 and IL-2 pathways and interacts with CD28 accessory signals to up-regulate growth of allospecific T cell lines.
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PMID:MHC class II molecules regulate growth in human T cells. 791 31

The regulation of the interleukin-4 receptor (IL-4R) was studied at mRNA and protein level in monocytic cells on stimulation with activators of different intracellular signaling pathways and IL-4. Activation of protein kinase C-dependent pathways with phorbol myristate acetate (PMA) or activation of protein kinase A-dependent pathways with DBcAMP and prostaglandin E2 resulted in an augmented IL-4R expression at mRNA and protein level. Transcriptional and posttranscriptional mechanisms seemed to be involved in the promotive effect of DBcAMP because the transcription rate increased 1.8-fold, and the half-life of IL-4R mRNA was prolonged to 150 minutes compared with 120 minutes in unstimulated cells. In contrast, the effect of PMA could only be ascribed to changes at transcriptional level. However, activation of Ca(2+)-dependent pathways with A23187 or stimulation with IL-4 had no effect on the IL-4R expression. The unresponsiveness to IL-4 could not be ascribed to a nonfunctional receptor because IL-4 did modulate the CD14, CD23, and HLA-DR antigen expression. These results are in contrast with IL-4R regulation in T cells, which is affected by IL-4- and Ca(2+)-dependent pathways. The discrepancy might be caused by the presence of the common IL-2 receptor gamma chain (gamma c) in T cells and the absence of the gamma c in monocytic cells, as has been shown by polymerase chain reaction. These data indicate that IL-4Rs are differentially regulated, depending on the cell type studied.
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PMID:Interleukin-4 receptor regulation in human monocytic cells. 802 87

Superantigens including staphylococcal enterotoxins (SE) bind to major histocompatibility complex class II molecules and interact with T cells bearing particular V beta chains. SEB was shown to induce the expression of interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha genes in human peripheral blood monocytes bearing HLA class II molecules. Monoclonal antibodies directed against HLA-DR and -DQ abolished the SEB-induced expression of both the IL-1 beta and TNF-alpha genes, suggesting that the HLA class II molecules mediated the gene expression. Therefore, we investigated the signal transduction mechanism responsible for the expression of IL-1 beta and TNF-alpha genes induced by binding of SEB to the HLA class II molecules. Three protein tyrosine kinase (PTK) inhibitors, genistein, herbimycin A, and tyrphostin, each of which has a different mechanism of action, strongly inhibited the expression of the monokine mRNA induced by SEB. Analyses of PTK activity revealed that SEB induced a rapid increase of membrane-associated PTK activity and this was blocked by tyrphostin. Furthermore, H-7 inhibited the expression of the monokine mRNA induced by SEB, suggesting the involvement of protein kinase C (PKC) in the signaling pathway. The involvement of PKC was confirmed by the observations that phorbol 12-myristate 13-acetate (PMA), a direct activator of PKC, induced the expression of the monokine mRNA and that SEB evoked the activation of membrane-associated PKC. Both activation of PKC and expression of the monokine mRNA induced by SEB appeared to be inhibited by tyrphostin, but those induced by PMA were not. Taken together, these findings indicate that both PTK and PKC play essential roles in HLA class II molecule-mediated signal transduction elicited by SEB and that PTK activation may precede PKC activation in the signaling pathway.
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PMID:HLA class II molecule-mediated signal transduction mechanism responsible for the expression of interleukin-1 beta and tumor necrosis factor-alpha genes induced by a staphylococcal superantigen. 825 34

Previous studies have suggested that gangliosides have an important role in cell signaling and recognition. However, their specific function in these processes has not been clearly defined. A mAb, R24, that reacts specifically with a cell surface ganglioside (GD3) has been demonstrated to stimulate proliferation of T cells derived from human peripheral blood. In this study, we have investigated the mechanisms by which the R24 mAb affects T cell functions. We have observed that the R24 mAb stimulates GD3+ T cell proliferation, cytotoxicity, and surface marker expression of IL-2R alpha-chain, IL-2R beta-chain, HLA-DR, CD11a, and CD11c. Additionally, IFN-gamma activity but not IL-1, IL-2, or IL-4 activity was present in culture supernatants 72 h after R24 stimulation. In some donors, increased IL-6 and TNF-alpha activity also was detected after R24 treatment. Furthermore, R24 treatment resulted in translocation of c-rel, but little or no NF kappa B p50 or p65, from the cytoplasm to the nucleus and an increase of NF kappa B binding complexes containing c-rel and p50. This treatment also caused increased tyrosine phosphorylation of specific protein substrates. R24-stimulated increases in proliferation, cytotoxicity, and cell surface protein expression could be blocked by cyclosporin and staurosporin, indicating that cyclophilin/calcineurin and protein kinase C may be involved in the R24 signaling pathway. Additionally, herbimycin A, a tyrosine kinase inhibitor, blocked the R24-stimulated increase in proliferation but not cytotoxicity at concentrations consistent with specificity for tyrosine kinases. These results suggest that multiple biochemical pathways are involved in the activation of human T cells by R24.
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PMID:Increased proliferation, cytotoxicity, and gene expression after stimulation of human peripheral blood T lymphocytes through a surface ganglioside (GD3) 828 32

The signal transduction pathways leading to the expression of IL-1 beta in human monocytes via HLA-DR stimulation were investigated. SEB, a staphylococcal enterotoxin that binds to HLA-DR molecules, induced IL-1 beta expression in human monocytes. Protein synthesis inhibition by cycloheximide did not inhibit SEB-mediated IL-1 beta signal, indicating that protein synthesis is not required for the MHC class-II-mediated IL-1 beta expression. The effect of PKC, PKA, and tyrosine kinase inhibitors on HLA-DR-mediated IL-1 beta mRNA expression was then determined. H7, a preferential PKC inhibitor, completely inhibited IL-1 beta signal induced by SEB. The role of PKC on HLA-DR-mediated IL-1 beta induction was further confirmed by the ability of SEB to activate PKC on monocytes directly when measured with labeled phorbol ester ([3H]Pbt2)-binding capacity of whole cells. HA 1004, a preferential PKA inhibitor, and isobutyl-methyl-xanthine (IBMX), which inhibits the degradation of cAMP, had no effect on SEB-induced IL-1 beta signal, excluding the role of cAMP on HLA-DR-mediated IL-1 beta expression. Two tyrosine kinase inhibitors, genistein and dihydroxycinnamate, both inhibited SEB-induced IL-1 beta mRNA in monocytes. SEB also induced enhanced tyrosine phosphorylation of several proteins in human monocytes when determined with antiphosphotyrosine immunoblotting. Our results demonstrate that both PKC and protein tyrosine kinases are involved in HLA-DR-induced IL-1 beta expression in human monocytes.
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PMID:Signal transduction mechanisms of HLA-DR-mediated interleukin-1 beta production in human monocytes. Role of protein kinase C and tyrosine kinase activation. 834 Feb 34


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