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)

Crosslinking HLA-DR molecules by monoclonal antibodies (moAbs) induces protein tyrosine phosphorylation and results in a secondary elevation of free cytoplasmic calcium concentrations in activated human T cells. Binding of bacterial superantigens or moAbs to DR molecules on activated T cells was recently reported to induce homotypic aggregation through activation of protein kinase C (PKC) and mediated by CD11a/CD54 (LFA-1/CAM-1) adhesion molecules. Here, we report that moAbs directed against framework DR, but neither DR1, 2- and DRw52- nor DQ- and DP-specific moABs induced homotypic aggregation of antigen- and alloantigen-activated T cells, antigen-specific CD4+ T-cell lines, a CD8+ T-cytotoxic cell line, and T-leukemia cells (HUT78). Protein tyrosine kinase (PTK) inhibitor herbimycin A partly blocked class-II-induced aggregation responses. In contrast, phorbol ester (PMA)-induced aggregation was essentially unaffected. A potent inhibitor of PKC, staurosporin, inhibited both moAb- and PMA-induced aggregation responses. The aggregation responses were completely inhibited by low temperatures, cytochalasins B and E, and partly inhibited by EDTA and CD18 moAbs, but unaffected by aphidicolin, mitomycin C, an adenylate cyclase inhibitor (2'5'-dideoxyadenosine), and moAbs against other adhesion molecules (CD2/CD58 [LFA-3], CD28/CD28 ligand B7, CD4, and CD44). In conclusion, HLA class-II-induced aggregation responses in activated T cells appear to involve PTK and PKC activation and to be mediated through CD11a-dependent and independent adhesion pathways.
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PMID:Signal transduction by HLA class II molecules in human T cells: induction of LFA-1-dependent and independent adhesion. 128 78

Neutrophil (PMN) activation by the yeast component zymosan involves the complement receptor type 3 (CD11b/CD18). Recombinant human tumour necrosis factor-alpha (rhTNF-alpha) augmented the zymosan-stimulated leukotriene B4 (LTB4) release from PMN, reaching a fourfold increase at 10(-9) M. Co-incubation of PMN with 10(-9) M rhTNF-alpha and staurosporine resulted in a further dose-dependent increase, which became significantly greater than a purely additive effect at a staurosporine concentration of 10 nM. This synergy was maintained at all doses of staurosporine tested. In addition, doses of phorbol 12-myristate 13-acetate (PMA) that do not activate protein kinase C (PKC) (below 10(-9) M) also augmented the zymosan-stimulated release of LTB4. However, doses of PMA above 10(-9) M progressively inhibited the response to levels below that of zymosan alone. Staurosporine at 50 nM completely prevented, and 10(-9) M rhTNF-alpha partially but significantly (P less than 0.02 at 10(-8) M PMA, P less than 0.01 at 10(-7) M PMA) reversed, this high-dose PMA inhibition. PKC activation thus opposes the priming effect of rhTNF-alpha on neutrophils, while PKC inhibition may enhance the ability of rhTNF-alpha to prime PMN for zymosan activation. The combined effect of rhTNF-alpha and staurosporine suggests an intracellular synergy rather than simply a direct action due to increased zymosan receptor expression. Thus there appear to be mechanisms whereby the responses of neutrophils may be augmented without activating PKC. Indeed, kinase activation may even exert a degree of feedback control that is antagonized by rhTNF-alpha treatment.
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PMID:Protein kinase C activation modulates tumour necrosis factor-alpha priming of human neutrophils for zymosan-induced leukotriene B4 release. 131 94

Although it is well accepted that intercellular adhesion involving the CD11a/CD18 (LFA-1) complex is critical in a wide array of T cell-dependent processes, recent demonstrations of an LFA-1 high avidity state, induced by triggering the T cell receptor (TCR) complex, has raised questions about the intracellular signals generated and molecular events leading to effective cell coupling, as well as their orderly sequence. In this study, we assessed the effects of T cell activation on the actin-based cytoskeleton, and LFA-1, as well as their interaction. Crosslinking the TCR complex with anti-CD3 mAb resulted in actin polymerization and colocalization with LFA-1, as detected by fluorescence microscopy. This association was confirmed by immunoprecipitating LFA-1 from the detergent insoluble, cytoskeletal-associated membrane fraction after TCR crosslinking. These consequences were inhibited by the protein kinase C (PKC) inhibitor staurosporine or by PKC desensitization, as was a transient CD11a hyperphosphorylation, induced by monoclonal anti-CD3. Furthermore, a small percentage of beta 2-deficient T cells maintained the ability to rearrange the cytoskeleton in response to TCR complex activation, with F-actin-VLA4 colocalization. These results provide evidence that the important consequences of TCR-induced signal transduction include a PKC-dependent cytoskeletal rearrangement, involving an association between leukocyte integrins and F-actin. We discuss the implications of these findings with respect to effective T cell functions.
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PMID:Antigen-receptor complex stimulation triggers protein kinase C-dependent CD11a/CD18-cytoskeleton association in T lymphocytes. 134 86

The leukocyte integrin LFA-1 (CD11a/CD18) plays a key role in many adhesive interactions involving cells of the immune system. Recently, it has been shown that LFA-1 is not only involved in cell adhesion, but that stimulation of LFA-1 can also contribute to cell activation. We now demonstrate that triggering of LFA-1 on T lymphocytes by monoclonal antibodies (mAb) against the LFA-1 alpha chain, but not against the LFA-1 beta chain, promotes cell adhesion. Induction of homotypic adhesion was only observed in T cells that had been pre-activated with anti-CD3 and not in resting peripheral blood T lymphocytes. The induced homotypic adhesion is mediated by LFA-itself, because it was inhibited by anti-LFA-1 beta mAb. This notion is supported by the temperature and divalent cation dependence which is characteristic of LFA-1-mediated adhesion. mAb against ICAM-1 (CD54) did not block LFA-1 alpha-induced adhesion. The sensitivity of LFA-1 alpha-induced adhesion to H7, which prevents the activation of protein kinase C and protein kinase A, and to cytochalasin B, which inhibits microfilament formation, suggests that the activation of the LFA-1 pathway through the LFA-1 alpha chain involves cell activation and requires an intact cytoskeleton.
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PMID:Induction of homotypic T cell adhesion by triggering of leukocyte function-associated antigen-1 alpha (CD11a): differential effects on resting and activated T cells. 135 99

Regulation of the avidity of LFA-1 (CD11a/CD18, alpha L beta 2) for its ligand ICAM-1 (CD54) was studied in human B cells by evaluating the effects of a phorbol ester, anti-IgM antibodies, staurosporine, and okadaic acid. We monitored changes in LFA-1 avidity by quantifying binding of cells to an immobilized rICAM-1 fusion protein. In this assay, the protein kinase C-activating phorbol ester PDB and anti-IgM antibodies, as well as the protein kinase inhibitor, staurosporine, were able to induce LFA-1-dependent binding to ICAM-1. This demonstrates that the high avidity state of LFA-1 can be induced by a protein kinase C-dependent and by a protein kinase C-independent pathway. Furthermore, treatment of the cells with the protein phosphatase inhibitor, okadaic acid, inhibited binding to ICAM-1. Treatment with staurosporine before addition of okadaic acid not only induced enhanced binding of cells to ICAM-1, but also dramatically reduced the ability of okadaic acid to inhibit binding. These results suggest a critical role for a protein phosphatase in inducing the high avidity state of LFA-1 as well as a role for a protein kinase in inducing the low avidity state of LFA-1.
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PMID:Regulation of LFA-1 avidity in human B cells. Requirements for dephosphorylation events for high avidity ICAM-1 binding. 135 24

The human monocytic cell line U937 was used as a model system to investigate the effects of glucocorticoids on monocytic differentiation. Upon incubation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (5 x 10(-9) M) for 48 to 72 h, the immature U937 cells ceased to proliferate and became morphologically and functionally macrophage-like. Preincubation of the cells with glucocorticoids (dexamethasone and prednisolone, 10(-7) and 10(-6) M) but not progesterone (10(-6) M) had marked effects: The cells remained in suspension and developed very little cell-cell interaction. This correlated with decreased expression of the surface molecules ICAM-1 and CD18 as determined by fluorescence-activated cell sorter analysis. The TPA-induced ability of the cells to release lysozyme or to generate reactive oxygen radicals (determined as reduction of nitroblue tetrazolium) was markedly reduced. The induction of cyclooxygenase activity and thus the ability to release prostanoids was almost completely abolished. Inhibition of prostanoid synthesis was also observed when the glucocorticoids were administered 24 or 48 h after TPA. The primary step of TPA induction, the activation and translocation of protein kinase C, however, was not affected by glucocorticoids as determined by activity measurements and Western blot analysis. There was no change in the subsequent TPA-induced induction of c-fos. The down-regulation of the differentiation-related oncogenes c-myc and c-myb was the same in cells treated with TPA in the presence or absence of glucocorticoids. Furthermore, no significant effect of glucocorticoids on the TPA-induced growth arrest was observed. Glucocorticoids thus interfere with TPA-induced functions, which are typical for activated macrophages; however, they do not impair the differentiation process and concomitant growth inhibition.
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PMID:Effects of glucocorticoids on the TPA-induced monocytic differentiation. 150 73

Recent attention has focused on the role keratinocytes (KC) may play in the induction of T cell-mediated inflammatory responses in skin, particularly because KC, when activated by immunologic stimuli, express MHC class II Ag and secrete immunomodulatory cytokines. We tested the capacity of normal human KC that were stimulated with PMA to induce PBMC proliferation. PMA-treated, but not untreated, KC induced proliferation of allogeneic as well as autologous PBMC; in addition, when purified CD4+ or CD8+ T cells were used as responders, each subset proliferated. PBMC proliferation was not due to direct action of PMA on PBMC, nor to contamination of KC cultures with Langerhans cells (LC) or dermal APC. Pretreatment with different protein kinase C inhibitors abrogated the capacity of PMA-stimulated KC to induce proliferation. Paraformaldehyde-fixed PMA-KC stimulated PBMC proliferation, whereas supernatants from PMA-treated KC failed to do so, indicating that a membrane-associated activity on PMA-KC contributes to the induction of PBMC proliferation. PMA induced intercellular adhesion molecule-1 (ICAM-1) expression on KC; furthermore, mAb against ICAM-1 or against its ligand lymphocyte function-associated Ag (LFA-1) (CD11a/CD18) significantly, but incompletely, reduced the stimulatory capacity of PMA-treated KC, indicating that ICAM-1/LFA-1 interaction contributed to PBMC proliferation. IFN-gamma or TNF-alpha also induced ICAM-1 on KC, but these KC failed to stimulate proliferation, suggesting that PMA induces additional signals from KC, which act in concert with ICAM-1 to promote proliferation. Finally, mAb against HLA-ABC or HLA-DR did not inhibit proliferation. We conclude that PMA can activate KC to stimulate T cell proliferation in a MHC-independent fashion. This activation is mediated by protein kinase C and in part by the induction of ICAM-1 expression on KC.
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PMID:Phorbol myristate acetate-activated keratinocytes stimulate proliferation of resting peripheral blood mononuclear lymphocytes via a MHC-independent, but protein kinase C- and intercellular adhesion molecule-1-dependent, mechanism. 167 Sep 43

Stimulation of PMN with inflammatory mediators markedly augments Fc and CR1 receptor-mediated ingestion. However, CD11/CD18-deficient PMN from three patients with complete leukocyte adhesion deficiency (LAD) failed to recruit phagocytic function in response to phorbol esters, cytokine, or Arg-Gly-Asp-containing ligand stimulation. Because stimulated ingestion is protein kinase C (PKC)-dependent, our data indicate that LAD PMN exhibit only PKC-independent phagocytosis. The defect in PKC-dependent ingestion is specific for CD11b/CD18 and not secondary to the chronic or recurrent infections which occur in this disease. The LAD phenotype for phagocytic function can be reproduced in normal PMN by the anti-CD11b MAbs OKM1 and OKM10. In contrast, MAb Mo1 (anti-CD11b) and MAb IB4 (anti-CD18) inhibit both CD11b/CD18-dependent and -independent mechanisms of ingestion by normal PMN. Their ability to inhibit CD11b/CD18-independent ingestion may be mediated by cAMP, as shown by experiments with a protein kinase A inhibitor HA1004 and by direct measurement of cAMP levels in immune complex- and FMLP-stimulated PMN. These data indicate that CD11b/CD18-independent and -dependent mechanisms of phagocytosis exist and that some effects of anti-CD11b/CD18 MAbs may be mediated by alterations in cAMP levels.
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PMID:Leukocyte adhesion-deficient neutrophils fail to amplify phagocytic function in response to stimulation. Evidence for CD11b/CD18-dependent and -independent mechanisms of phagocytosis. 167 46

Leukocyte adhesion deficiency (LAD) is an inherited disorder of leukocyte function that is caused by defects in the CD18 gene and is associated with diminished cell surface expression of CD11/CD18 proteins. We have developed an in vivo model for gene therapy of LAD. Recombinant retroviruses were used to transduce a functional human CD18 gene into murine bone marrow cells which were transplanted into lethally irradiated syngeneic recipients. A reliable flow cytometric assay for human CD18 in transplant recipients was developed based on: (a) the availability of human specific CD18 monoclonal antibodies and (b) the observation that human CD18 can form chimeric heterodimers with murine CD11a on the cell surface. Human CD18 was detected on leukocytes in a substantial number of transplant recipients for at least 6 mo suggesting that the gene had been transduced into stem cells. Expression was demonstrated in several lineages of a variety of hematopoietic tissues, but was consistently highest and most frequent in granulocytes. Murine granulocytes demonstrated appropriate posttranscriptional regulation of human CD18 in response to activation of protein kinase C. No apparent untoward effects of human CD18 expression were noted in transplant recipients. These studies suggest a specific strategy for LAD gene therapy that may be effective and safe.
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PMID:An in vivo animal model of gene therapy for leukocyte adhesion deficiency. 168 Aug 82

Adhesion of activated leukocytes to cells is of critical functional importance. The adhesion is known to be mediated mainly by the CD11/CD18 integrins, also known as leukocytic cell adhesion molecules, or Leu-CAM. We have now studied the phosphorylation of Leu-CAM by protein kinase C and the correlation of phosphorylation with the generation of the adhesive phenotype among human peripheral blood mononuclear leukocytes during cell activation. We here show that a good correlation exists between the phosphorylation of the beta subunit of Leu-CAM (CD18), and the extent of cell-to-cell adhesion. The phosphorylated CD18 subunit was associated with both CD11a and CD11b. Purified protein kinase C was able to phosphorylate the beta subunit of isolated Leu-CAM in vitro. The phosphorylation occurred mainly on serine residues.
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PMID:Phosphorylation of the beta-subunit of CD11/CD18 integrins by protein kinase C correlates with leukocyte adhesion. 168 56


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