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)

Staphylococcus enterotoxins and toxic shock syndrome toxin-1 (TSST-1) are members of the family of staphylococcal exoproteins (SE) which binds specifically to HLA class II molecules and certain V beta T cell receptor phenotypes. These bacterial products have been termed "superantigens" due to their capacity to stimulate a greater proportion of T lymphocytes than peptide antigens without a requirement for antigen processing. The SE stimulate monocytes to secrete IL-1 and TNF-alpha and affect B lymphocyte proliferation in response to anti-human IgM and Ig production by PBMC. The current study concerns the transmission of signals in human B lymphocytes following fixation of TSST-1. Activation of both PLC and PKC are observed while intracellular calcium levels remain unchanged. Levels of HLA class II mRNA were increased suggesting that a pathway leading to activation was triggered. This study therefore identifies some of the second messengers involved after SE fixation on HLA class II molecules and suggests that the signals transmitted via class II antigens as well as those via the TCR may have a role in the physiological responses to bacterial superantigens.
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PMID:Bacterial superantigen signaling via HLA class II on human B lymphocytes. 802 2

MHC class II molecules play a central role in the control of the immune response, but their biologic function and mechanism of action on the surface of activated human T lymphocytes are not entirely understood. In our study, the functional role of HLA class II molecules in T-blast proliferation was investigated by analyzing in parallel the IL-2- and CD3-driven activation pathways. The results indicate that the cross-linking of class II and CD3 molecules significantly increased the CD3-mediated T-blast proliferation, while no effect was observed on the IL-2-driven cell activation. This phenomenon was not confined to either CD4+ or CD8+ subsets nor was specifically affected by CD45 triggering. Biochemical studies showed that signaling via MHC class II molecules in T blasts led to PKC membrane translocation and IP accumulation. The simultaneous triggering of CD3 and HLA class II molecules led to a synergistic effect on IP accumulation but did not increase the CD3-mediated PKC membrane translocation. Our data suggest that HLA class II molecules are involved in T-cell-T-cell interactions and can mediate accessory signals, affecting the T-lymphocyte activation state.
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PMID:HLA class II molecules transduce accessory signals affecting the CD3 but not the interleukin-2 activation pathway in T blasts. 813 20

HLA class II antigens are involved in signal transduction in B lymphocytes. We have previously reported that the ligation of HLA class II antigens in B cells results in an increase of cytosolic and membrane PKC activity [3]. Unlike TPA, no translocation of the cytosolic PKC was observed following anti HLA class II antibody treatment. However, an increase of both PKC activity (cytosolic and membrane) and quantity was observed. These effects are completely abolished by actinomycin D treatment. Northern blot analysis and PCR reaction revealed that anti HLA class II antibodies induce an increase of the PKC beta level which is significant after 20 minutes of stimulation and rose to a maximum after 60 minutes. Taken together, our results show that anti HLA class II antibodies exert a transcriptional regulation of PKC in human B lymphocytes.
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PMID:[Demonstration of transcriptional regulation of protein kinase C by class II anti-HLA antibodies in human CA cells of the lymphoblastoid line]. 820 57

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

The class II human leucocyte antigens (HLA class II) are principally peptide presentation molecules. Signal transduction by these molecules has also been shown to transmit activation signals in both B and T lymphocytes by a pathway including protein tyrosine kinase activation, an intracellular calcium flux, and both the activation and transcriptional regulation of protein kinase C (PKC) isoforms. Apoptosis can also result from human leukocyte antigen class II stimulation. Inhibitors of gene transcription were used to inhibit activation and, therefore, to distinguish the signal transduction pathways important for apoptosis. This approach provided evidence that cellular activation and apoptosis undertook separate signaling pathways, and that PKC and intracellular calcium were shared between the two pathways, while tyrosine kinase activity was essential for cell activation. Further studies using cord blood B cells showed that these cells were incapable of generating a calcium flux after HLA class II ligation and were not subject to cell death. The importance of sustained levels of calcium for programmed cell death (PCD) was underlined since the restoration of a calcium flux enabled PCD of cord blood B cells via HLA class II. These results demonstrate that HLA class II stimulation initiates two distinct signal transduction pathways.
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PMID:HLA class II signaling mediates cellular activation and programmed cell death. 891 87

The class II human leukocyte antigens (HLA class II) are constitutively expressed on antigen presenting cells (APC) and are essential for peptide presentation to helper T lymphocytes. Signal transduction by HLA class II molecules on B lymphocytes has been described and has been shown in many cases to induce cellular proliferation. However, since signalling via HLA class II can also lead to apoptosis, it has not been clear how the outcome of the signals is determined. We have distinguished two separate HLA class II-initiated pathways leading to either proliferation or apoptosis of primary human B lymphocytes. Proliferation requires new gene transcription and activation of src family tyrosine kinases. In contrast, apoptosis is significantly increased in the absence of transcription/translation. It is dependent on serine/threonine phosphatases and cytoskeletal mobility. An extracellular source of calcium was essential for apoptosis, suggesting the need for sustained high level of intracellular calcium. Activation of iso-enzymes of the protein kinase C family was needed for both pathways. We therefore conclude that HLA class II molecules can initiate two distinct signalling pathways leading to either proliferation or apoptosis of APC.
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PMID:HLA class II molecule signal transduction leads to either apoptosis or activation via two different pathways. 896 75

Protein kinase inhibitors staurosporine and CGP 41251, a benzoylated derivative of staurosporine with selective PKC inhibitory activity, reversed the decreased rhodamine 123 uptake in HL-60/VCR (with Pgp-mediated drug resistance) but not in HL-60/ADR (MRP-mediated drug resistance) cells. CGP 41251 reversed the decreased rhodamine 123 uptake in HL-60/VCR cells more efficiently (when compared on a equimolar basis) than staurosporine. However, the protein tyrosine kinase inhibitor genistein unexpectedly modulated the decreased rhodamine 123 uptake in Pgp positive (HL-60/VCR) cells, but not in HL-60/ADR (MRP positive) cells. Cell surface phenotype of both HL-60 drug-resistant cell sublines was compared with that of the parental, drug-sensitive HL-60 cells. Both drug-resistant cell lines expressed markedly decreased levels of cell surface HLA class I antigen in comparison with the parental HL-60 cells. A similar decreased cell surface expression of HLA class II/DR on both drug-resistant, as well as of CD59 (protectin) on HL-60/ADR cells was found. Both protein kinase C inhibitors studied (staurosporine and CGP 41251) exhibited variable effects on cell surface antigen (HLA, ICAM-1, CD59) expression, suggesting complex interactions between PKC-dependent and -independent mechanisms in the regulation of surface antigen expression in these cell lines. Staurosporine differed from CGP 41251 in the cell cycle alterations induced in the HL-60 cell lines examined. Staurosporine induced the accumulation of cells in the G2/M phase of the cell cycle and the appearance of pre-G0 (apoptotic) cells in both examined drug-resistant cell lines. Staurosporine induced the appearance of cells with high DNA content in HL-60/ADR, but not in HL-60/VCR cells.
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PMID:Protein kinase inhibitor-induced alterations of drug uptake, cell cycle and surface antigen expression in human multidrug-resistant (Pgp and MRP) promyelocytic leukemia HL-60 cells. 922 74

This study was undertaken to investigate the effects of propranolol, IFN-beta, and the protein kinase modulators on IFN-gamma induction of MHC class II antigen expression and cytokine production in THP-1 human monocytic cells. IFN-gamma induced expression of HLA-DR and DQ molecules and secretion of the monokines IL-1 beta and TNF-alpha in THP-1 cells in a time and dose-dependent manner. The effect of INF-gamma on class II HLA antigens was dose-dependently inhibited by IFN-beta. H-7, phloretin, staurosporine as well as GF 109203X are selective enzyme inhibitors of protein kinase C (PKC), down-regulating IFN-gamma induced MHC class II expression and cytokine production. Stimulators of PKC, like PMA, replaced IFN-gamma in the induction of monokines in THP-1 cells, whereas the addition of HA 1004 or arachidonic acid to the culture had no effect on IFN-gamma mediated changes. Blocking of phospholipase D (PLD)-derived diacylglycerol (DAG) formation by propranolol abrogated IFN-gamma increased HLA class II expression and IL-1 beta secretion, but had little effect on IFN-gamma induced TNF-alpha production. These findings appear to suggest that PLD-derived phosphatidate is not the primary source of DAG production in IFN-gamma-induced TNF-alpha secretion, but may be necessary for IFN-gamma-mediated MHC class II induction and IL-1 beta production in human monocytes, whereas phospholipase A2 may not be required for IFN-gamma activation of PKC in the process.
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PMID:Effect of propranolol and IFN-beta on the induction of MHC class II expression and cytokine production by IFN-gamma IN THP-1 human monocytic cells. 954 99

Cord blood is increasingly used for hematopoietic stem cell transplantation since less severe graft-versus-host disease has been reported leading to the notion that cord blood is "naive." Human leucocyte antigen (HLA) class II molecules are expressed throughout B lymphocyte ontogeny (except the plasmocytes), are responsible for antigen presentation, and can also transmit signals. Cord blood B stimulate an allogeneic response, and this property is believed to indicate the presence of a class II-associated peptide. In this study we examined the capacity of cord blood B to transmit signals via HLA-DR. Activation and relocalization of protein kinase C (PKC) isoenzymes alpha and betaII was detected along with tyrosine kinase activation and proliferation. However, in contrast to resting adult B, generation of an intracellular calcium ([Ca++]i) flux and rapid aggregation were not detected. To address the question of whether or not HLA-DR signals throughout B lymphocyte ontogeny, we extended this study to include malignant adult B (B chronic lymphocytic leukemia [B-CLL], B mantle cell lymphoma, and B large cell leukemia). Tyrosine kinase activation and proliferation were observed in all these cell populations, albeit in the absence of [Ca++]i flux or an increase in PKC. HLA-DR therefore transmits signals throughout B lymphocyte ontogeny, although different signaling pathways are initiated in adult vs. fetal vs. malignant B. The lack of intracellular [Ca++]i flux in both cord blood and malignant B lymphocytes may represent a feature of HLA class II signaling at a particular stage of differentiation, although the downregulation of PKC clearly distinguishes between cord blood B and B-CLL.
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PMID:Signal transduction via human leucocyte antigen class II molecules distinguishes between cord blood, normal, and malignant adult B lymphocytes. 969 9

Susceptibility to several disorders, including insulin-dependent diabetes mellitus and multiple sclerosis, has been associated with alleles of HLA class II genes and loci in the TNF cluster in the central major histocompatibility complex (MHC) region. As recombination within this region is rare, it is difficult to determine which genes are important. This will be facilitated by the identification of functional polymorphisms. Hence we are sequencing reverse transcription-polymerase chain reaction products derived from central MHC genes in well characterized and conserved ancestral haplotypes. Here we address the IKBL gene, which lies near the TNF cluster at the telomeric end of the central MHC. Although the IKBL cDNA sequence was conserved between most ancestral haplotypes, a synonymous nucleotide substitution, a 3' untranslated region substitution, and a single nonsynonymous substitution were identified. The latter (IKBL+738) was present in multiple examples of the 7.1 haplotype [HLA-A3, B7, DR2 (DR15)] and resulted in a cysteine to arginine substitution in a predicted protein kinase C phosphorylation site. This polymorphism did not occur in 18 other common haplotypes from the 10th International Histocompatibility Workshop and thus appears haplospecific. A role for IKBL+738 in the association between HLA-A3,B7,DR2(DR15) and susceptibility to multiple sclerosis is discussed.
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PMID:The central MHC gene IKBL carries a structural polymorphism that is associated with HLA-A3,B7,DR15. 1036 24


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