When murine thymocytes were stimulated by mitogens such as concanavalin A, the Ca2+ ionophore A23187, or 4j-phorbol 12-myristate 13-acetate, there was a marked increase of 32p incorporation into immunoprecipitable lipomodulin, a phospholipase inhibitory protein. These compounds enhanced 45Ca21 influx into thymocytes, which, in turn, increased protein phosphorylation, probably by Ca2+-and phospholipid-dependent protein kinase (protein kinase C). Cyclic 8-bromo-AMP, an inhibitor of lymphocyte mitogenesis, blocked the mitogen-stimulated phosphorylation of lipomodulin, although it stimulated the protein phosphorylation via cyclic AMP-dependent kinase (protein kinase A). On electrophoresis, the hydrolysates of 35P-labeled lipomodulin showed a single radioactive spot, which comigrated with authentic phosphotyrosine. The partially purified middle-sized tumor antigen was able to phosphorylate lipomodulin after being phosphorylated by protein kinase C but not by the catalytic subunit of protein kinase A. Our findings suggest that the activity of a tyrosine-specific kinase, which phosphorylates lipomodulin in vivo as well as in vitro, is stimulated by protein kinase C and inhibited by protein kinase A.
The activity of phospholipase inhibitory protein, lipomodulin, partially purified from rabbit neutrophils, was markedly decreased after treatment with sera from patients with rheumatic diseases such as systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis. The decrease of the protein's inhibitory activity on phospholipase A2 paralleled the amount of [35S]methionine-labeled lipomodulin precipitated by the sera. Absorption ofpatients' sera with anti-human IgM (,u chain) or protein A-agarose, but not with anti-human IgG (ychain), decreased their ability to decrease. the activity of lipomodulin on phospholipase A2 or to precipitate the radioactive li omodulin. The IgM fraction of patients' sera could precipitate [ S]methionine-labeled lipomodulin (40,000 daltons) which comigrated with highly purified Iipomodulin on gel electrophoresis with sodium dodecyl sulfate. All of these observations suggest that the sera of many patients with rheumatic diseases contain autoantibody against lipomodulin. A monoclonal antibody against lipomodulin was also obtained. Stimulating human fibroblasts with bradykinin in the presence of monoclonal antilipomodulin antibody markedly enhanced arachidonic acid release due to the activation of phospholipase(s) in the intact cells, and this stimulatory effect was blocked by adding purified lipomodulin. These findings suggest that lipomodulin regulates the activity of phospholipase(s) on the cell surface and that autoantibodies against lipomodulin may play a role in certain symptoms of rheumatic diseases, especially by the formation of prostaglandins and other metabolites of arachidonic acid.A phospholipase A2 inhibitory protein, which we propose to name "lipomodulin," was recently isolated from neutrophils treated with glucocorticoids (1). This protein was found to inhibit phospholipase A2 (phosphatide 2-acylhydrolase, EC 3.1.1.4), an enzyme that cleaves the ester bond in the A3-position of phosphatidylcholine, to liberate unsaturated fatty acids (mainly arachidonic acid) and lysophosphatidylcholine. Lipomodulin was shown to be induced by glucocorticoids in a receptor-mediated fashion (1). The inhibitory action of glucocorticoids on prostaglandin formation has been assumed to be due to induction of this inhibitory protein, which decreases the availability of the precursor ofprostaglandins, arachidonic acid, by inhibiting phospholipase A2 (1, 2).Recently, autoantibodies for cell surface molecules have been detected in patients with myasthenia gravis, Graves disease, insulin-resistant diabetes, or asthma (3-6). These antibodies are assumed to be closely related to the pathogenesis of the symptoms that these diseases produce. Because prostaglandins and hydroxyl compounds of arachidonic acid are thought to play a role in the pathophysiology of rheumatic diseases (7), we initiated a search for autoantibodies against lipomodulin.We report here the presence of autoantibodies against lipomodulin, a cell surface protein, in the sera of many patients with rheumatic diseases su...
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