Presence of autoantibody for phospholipase inhibitory protein, lipomodulin, in patients with rheumatic diseases.

Abstract

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...

An overview of the effects of annexin 1 on cells involved in the inflammatory process

“…Subsequent work demonstrated the ability of this cell type to respond to GC incubation with over-expression of ANXA 1 (Phillips et al 1989). Consistently, anti-ANXA1 antibodies reversed the inhibitory effect of dexamethasone on arachidonate release (Hirata et al 1981). Activation of human skin fibroblasts provokes intracellular re-location of several annexins, including ANXA1 (Barwise et al 1996), probably with the ultimate effect of controlling cell activation and lipid metabolism (Errasfa et al 1985).…”

“…Fibroblast/ Synoviocyte -The original work of Hirata et al (1981) described the ability of inhibiting phospholipase A 2 activity in stimulated 3T3 mouse fibroblasts by a purified preparation of ANXA1. Subsequent work demonstrated the ability of this cell type to respond to GC incubation with over-expression of ANXA 1 (Phillips et al 1989).…”

Glucocorticoids Induce the Formation and Release of Anti‐inflammatory and Anti‐phospholipase Proteins Into the Peritoneal Cavity of the Rat

“…Isolation of anti-phospholipase proteins Hirata et al (1980Hirata et al ( , 1981 found that their antiphospholipase protein (lipomodulin) could be purified using a combination of DEAE cellulose and G-75 Sephadex chromatography. We have also found that these techniques are effective for the isolation of the anti-phospholipase protein fractions from the crude peritoneal proteins.…”

“…By inhibiting phospholipase A2, certain steroids prevent the biosynthesis by cells of pro-inflammatory mediators such as the prostaglandins, hydroxy-acids and leukotrienes (Gryglewski, Panczenko, Korbut, Grodzinska & Ocetkiewicz, 1975;Hong & Levine, 1976; Nijkamp, Flower, Moncada & Vane, 1976;Tam, Hong & Levine, 1977;Blackwell, Flower, Nijkamp & Vane, 1978;Flower & Blackwell, 1979;Di Rosa & Persico, 1979;Hirata, Schiffman, Venkatasubramanian, Salomon & Axelrod, 1980;Blackwell, Carnuccio, Di Rosa, Flower, Parente & Persico, 1980; Hirata, Del Carmine, Nelson, Axelrod, Schiffman, Warabi, De Blas, Nirenberg, Manganiello, Vaughan, Kumagai, Green, Decker & Steinberg, 1981;Carnuccio, Di Rosa, Flower & Pinto, 1981). This effect is specific for the glucocorticoids (Hong & Levine, 1976;Nijkamp etal., 1976;Tam etal., 1977;Blackwell et al, 1978;Flower & Blackwell, 1979;Di Rosa & Persico, 1979;Carnuccio et al, 1980;Hirata etal., 1980;Blackwell et al, 1980;Hirata etal., 1981), and depends upon receptor occupation as well as transcriptional and translational events within the target cells (Danon & Assouline, 1978;Russo-Marie, Paing & Duval, 1979;Flower & Blackwell, 1979;Di Rosa & Persico, 1979;Carnuccio et al, 1980;Hirata etal., 0007-1188/82/050185-10 $01.00 1980; Blackwell etal., 1980;Hirataetal., 1981).…”

“…We have isolated this substance from rat peritoneal leucocytes (where it is apparently stored) and shown it to be a polypeptide of 15k mol.wt.-'Macrocortin' (Blackwell et al, 1980); a protein of 40kmol.wt. ('Lipomodulin') having many similar properties has also been isolated from steroid-stimulated rabbit polymorphonuclear leucocytes by Hirata et al (1980Hirata et al ( , 1981.…”