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)

The specificity and properties of a novel IgA receptor expressed on the surface of a tissue culture-adapted B cell lymphoma, T560, that originated in murine gut-associated lymphoid tissue, have been explored. Like the IgA receptors of murine T and splenic B cells studied by others, the T560 IgA receptor is trypsin sensitive and neuraminidase resistant and is up-regulated on T560 cells by exposing them overnight to high concentrations of polymeric IgA. Unlike them, the T560 IgA receptor is inhibited by low concentrations of IgM and high concentrations of IgG2a and IgG2b, binds at pH 4.0 but not at pH 8.0, is down-regulated by activation of protein kinase C and is sensitive to phosphatidylinositol-specific phospholipase C, indicating that it is glycosyl phosphatidylinositol-linked to the cell membrane. It is not a cell-bound form of galactosyl transferase, does not appear to bind to Ig through carbohydrate residues and does not react specifically with antibody to secretory component. It may be a completely new, cross-reactive receptor, perhaps related in some way to the polymeric Ig receptor or to the receptor for IgA expressed on the apical surface of Peyer's patch M cells, which is known to cross-react with IgG. Alternatively, it may be homologous to the highly IgA-specific Fc alpha R of T cells but, perhaps because of its glycosyl phosphatidylinositol linker, may have an ability to move and interact with other Ig receptors on the cell surface such that Ig bound to them are cross-inhibitory.
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PMID:A novel IgA receptor expressed on a murine B cell lymphoma. 137 46

We have previously demonstrated that activation of protein kinase C (PKC) by phorbol esters induces selectively IgA synthesis by mouse B cells. In this study, we investigated the effects of a number of protein kinase inhibitors on IgA secretion induced by a recombinant murine IL-5 in LPS-stimulated mouse B cells. The results show that PKC inhibitors, such as sphingosine (SPH), staurosporine (STP) and H-7, blocked IL-5-induced IgA synthesis; the protein kinase A inhibitor HA-1004 and the inhibitor of calcium/calmodulin dependent protein kinase W-7 had no effect on IgA secretion induced by IL-5. The proliferation of the IL-5 sensitive B13 cell line in response to IL-5 was also inhibited by addition of SPH or STP or H-7. The data suggest an involvement of the PKC pathway in IL-5-induced B cell differentiation into IgA secreting cells.
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PMID:IL-5-induced IgA synthesis by LPS-stimulated mouse B cells is prevented by protein kinase C inhibitors. 158 1

Following incubation of murine epidermis in medium containing either interleukin-2 or interleukin-6, there is significant upregulation in the density of Ia+ epidermal Langerhans cells (to 159% and 175% of control, respectively). This cytokine-induced upregulation is abrogated by either rabbit or human IgG due to triggering of Fc gamma receptors. In contrast, human IgA does not inhibit the effect of interleukin-2 or interleukin-6. Using different isotypes of murine IgG, we have demonstrated that all subclasses are capable of inhibiting the cytokine-induced enhancement of Ia antigen, although IgG1 and IgG2b must be heat aggregated to be effective. The IgG-mediated events are dependent on prostaglandin synthesis because they can be blocked by the cyclooxygenase inhibitor indomethacin, 10 micrograms/ml. The responsible PG appears to be PGD2; in contrast to its known inhibitory effect on macrophages, PGE2 does not inhibit the upregulation of Ia antigen on Langerhans cells. In addition, these IgG-mediated events are dependent upon the generation of cAMP because they can be blocked by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, 1 mM. Despite the apparently central role of PGD2 and cAMP in this process, triggering of the Fc gamma R by different isotypes of IgG blocks upregulation of Ia via at least two different pathways. The inhibition caused by aggregated IgG1 or IgG2b, which bind to Fc gamma RII on Langerhans cells, is abrogated by para-bromophenacylbromide, an inhibitor of phospholipase A2. In contrast, the inhibition caused by monomeric IgG2a, which binds to Fc gamma RI most likely on keratinocytes, or monomeric IgG3, which probably binds to this same Fc gamma RI, is abrogated by staurosporine, an inhibitor of protein kinase C, as well as by W7, a calmodulin antagonist. Finally, 1,2 dioctanoyl-rac-glycerol, an activator of protein kinase C, mimics the Ig-mediated events. Based on these findings, as well as studies using monoclonal antibodies to the murine Fc gamma receptors I and II, we conclude that, as is the case in murine macrophages, triggering of an epidermal Fc gamma RI, most likely on keratinocytes, results in the generation of cAMP via a Ca(++)-dependent protein kinase C pathway, whereas triggering of an epidermal Fc gamma RII, most likely on Langerhans cells, results in the elevation of cAMP via a phospholipase A2-mediated pathway. In contrast to the situation for macrophages, PGD2 is a vital intermediate in both pathways, perhaps because Langerhans cells have receptors for only this prostaglandin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of triggering epidermal Fc gamma receptors on the interleukin-2- and interleukin-6-induced upregulation of Ia antigen expression by murine epidermal Langerhans cells: the role of prostaglandins and cAMP. 165 69

A GALT-derived B lymphoma, T560, that bears IgAR is described. T560 is IgG2a kappa +, Ia+, B220+, J11d+, Thy-1-, CD3-, CD4-, CD5-, Mac 1-, Mac 2-, nonspecific esterase negative and binds bromelain-treated mouse RBC but not SRBC or ORBC. It presents antigen, secretes IL-1, IL-4 and IL-6 but not IL-2, IL-5 or TGF beta and appears to be related to the Lyt 1+(CD5) lineage of B cells though it lacks Lyt 1. T560 bears IgAR that, on the cell surface, are completely cross-inhibited by low concentrations of IgM and by high concentrations of IgG2a and IgG2b. They do not appear to represent a cell-surface form of galactosyl transferase. They are inducible by high concentrations of IgA, sensitive to trypsin and insensitive to neuraminidase. They are down-regulated by activation of PKC with PMA, but their recovery is not inhibited by cycloheximide, indicating that they are not degraded or shed. They may either lose their affinity for IgA or be internalized without degradation. Seventy percent of IgA receptor activity is lost when T560 is treated with PI-PLC; part of this loss of activity is due to activation of PKC and is inhibited by staurosporine, but approximately 30% of it is not protected by staurosporine indicating that some, or all, of the IgA receptor of T560 is connected to the cell membrane via a GPI linker. The T560 IgA receptor could be related to the poly-Ig or M cell receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sensitivity of receptors for IgA on T560, a murine B lymphoma, to phorbol myristate acetate and to phosphatidylinositol-specific phospholipase C. 165 5

To understand mechanisms of signal transduction involved in the regulation of isotype differentiation of B lymphocytes, we investigated effects of activation of protein kinase C (PKC) by phorbol esters and elevation of intracellular free calcium (Ca2+) by the calcium ionophore ionomycin (Ion) on Ig secretion by mouse Peyer's patch (PP) and spleen B cells. Results show that Ion suppressed production of IgM, IgG, and IgA by LPS-stimulated B cells whereas PKC-activating phorbol esters also inhibited LPS-induced IgM and IgG secretion, but induced a substantial IgA synthesis, as well as alpha-chain mRNA transcription, in B cells whether stimulated or not by LPS. Phorbol esters enhanced IgA response by directly activating PKC, inasmuch as the other phorbol ester, 4 alpha-phorbol 12,13-didecanoate, which is inactive with respect to PKC, had no effect on B cell differentiation. The increase in IgA secretion occurred in whole PP B cells, but not in the membrane IgA- B cell subset, suggesting that PKC activation does not promote the switching rate of IgM+ cells to IgA+ cells. Results from double staining studies of mIgA using FITC-labeled anti-IgA antibodies and DNA content using the DNA-binding propidium iodide showed that enhanced IgA response was not caused by IgA B cell clonal expansion. PMA induced low level of IL-6 production by highly purified PP B cells. However, addition of anti-mouse IL-6 antibody did not prevent PMA-enhanced IgA secretion, suggesting that IL-6 was not responsible for IgA induction by PMA. Collectively, the present data demonstrate that PKC activation and Ca2+ mobilization, which synergistically trigger cell proliferation, have differential effects on B cell isotype differentiation. Elevation of intracellular Ca2+ suppresses Ig production, but activation of PKC selectively enhances IgA secretion by directly promoting terminal differentiation of IgA-committed PP B cells into IgA-secreting plasma cells.
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PMID:Selective induction of high levels of IgA synthesis in Peyer's patch B cells by protein kinase C-activating phorbol esters. 190 30

In the present study, we demonstrate that the PKC-activating phorbol ester PMA selectively induced IgA synthesis by PP B cells. PKC activation triggered neither B cell proliferation nor the switching rate of IgA- to IgA+ cells. Together with the fact that the rate of IgA secretion by the myeloma cell line MOPC 315 was not altered by PMA, the data demonstrate that activation of PKC enhances IgA secretion by promoting terminal differentiation of IgA-committed B cells into IgA-secreting plasma cells.
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PMID:Role for protein kinase C activation in IgA B cell terminal differentiation. 195 71

Entamoeba histolytica, a cause of invasive colitis or liver abscess, is responsible for substantial worldwide morbidity and mortality. An understanding of the biochemical basis for the parasite adherence and cytolytic activities and antiamebic host immune response mechanisms are prerequisites for vaccine development. The E. histolytica galactose (Gal) or N-acetyl-D-galactosamine (GalNAc) inhibitable adherence lectin mediates attachment of trophozoites to colonic mucins or mammalian target cells. Amebic cytolysis of target cells requires Gal/GalNAc-lectin-mediated adherence, parasite phospholipase A activity, and maintenance of an acid pH in amebic intracellular vesicles. Cytolytic activity is stimulated by phorbol esters (activators of protein kinase C) and results from an E. histolytica-mediated increase in free Ca++ within the target cell. The Gal/GalNAc adherence lectin is a highly conserved antigen that is universally recognized by human immune sera; patients cured of invasive amebiasis possess antigen-specific cell-mediated immunity effective in vitro against E. histolytica trophozoites. Promising vaccines include the purified adherence lectin, for eliciting an intestinal secretion of IgA antibody to lectin, and additional E. histolytica antigens, which elicit cell-mediated amebicidal responses.
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PMID:Entamoeba histolytica: from adherence to enteropathy. 253 86

A novel murine B lymphoma expressing membrane-associated IgA was isolated and used to compare mechanisms of signal transduction by sIgM and sIgA. Like other isotypes so far studied, crosslinking of sIgA by anti-immunoglobulin antibodies stimulates hydrolysis of inositol phospholipids and causes elevation of intracellular free calcium. Furthermore, signals generated through sIgA are coupled to elevation of c-fos proto-oncogene expression. Coupling appears to be through the protein kinase C rather than through the Ca2+ component of sIg signalling as phorbol diester, but the Ca2+ ionophore cannot mediate this effect. Thus these results, coupled with those from earlier studies, show that early signal transduction through surface immunoglobulin appears to be similar regardless of the particular isotype involved in binding ligand.
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PMID:Signalling through sIgA on a novel murine B lymphoma. 255 Aug 16

A B-cell subpopulation (BM-A cell) responding to an antigen with the production of IgM and IgA plaque-forming cells but not of IgG plaque-forming cells was isolated from neonatally bursectomized chickens and was examined for the mode of activation by B-cell mitogens. The BM-A cells did not elevate both glucose consumption and protein synthesis with the B-cell mitogens, in striking contrast to normal B cells. The BM-A cells were also not activated by an activator of protein kinase C, phorbol myristate acetate. Both anti-Ig and a calcium ionophore, A23187, however, primed the BM-A cells to increase intracellular free calcium ion as well as normal B cells. From these results it is conceived that the lack of protein kinase C activation may be responsible for the failure of activation of BM-A cells.
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PMID:Characterization of activation of a partially defective B cell subpopulation with immunocompetence restricted to IgM and IgA. 278 31

We describe a 27-year-old white man with common variable immunodeficiency (CVID) who has two healthy histoidentical brothers and one IgA-deficient sister who shares one HLA haplotype with the patient. T cells from the patient with CVID showed an impaired response to recall antigens (tetanus toxoid, E. coli), whereas his IgA-deficient sister and his two healthy histoidentical brothers responded normally. Cross-mixing experiments using isolated monocytes and T cells from the CVID patient and one histoidentical brother revealed that the patient's monocytes were fully functional in processing and presenting antigen to resting T cells of his brother, and provided normal accessory cell function for superantigen-induced activation of his brother's resting T cells. In contrast, the patient's T cells were unable to respond to antigen presented by the brother's monocytes and failed to respond with an increase in intracellular free Ca++ to stimulation with superantigen, which is known to bind to the TCR V beta-chain outside the antigen-binding groove. However, stimulation with a combination of PMA and IM, directly activating protein kinase C and increasing intracellular free Ca++ by bypassing membrane receptors, induced normal Ca++ flux. These data indicate that the patient with CVID has a defect in TCR-mediated signalling at the level of the T cells which is not present in his histoidentical healthy brothers or in his haploidentical IgA-deficient sister.
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PMID:Impaired TCR signal transduction, but normal antigen presentation, in a patient with common variable immunodeficiency. 781 63


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