Monocyte chemoattractant protein 1 and interleukin 8 production by rheumatoid synoviocytes. Effects of anti-rheumatic drugs.
Activated synoviocytes are major effector cells in the pathogenesis of rheumatoid arthritis (RA) because of their capacity to secrete a variety of inflammatory mediators. Among these mediators, the chemotactic proteins monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8) are likely to contribute to the recruitment of inflammatory cells into the arthritic joint. We examined the effects of anti-rheumatic drugs on the MCP-1 and IL-8 production by cultured RA synoviocytes exposed to pro-inflammatory agonists. Both chemotactic cytokines were quantified by specific enzyme-linked immunosorbent assays (ELISA), and found to accumulate in the culture supernatants. Although the time course of formation was similar, the yield of IL-8 was three to 10-fold higher than that of MCP-1. Non-steroidal anti-inflammatory drugs inhibited the synthesis of prostaglandins, but did not influence the production and release of both chemotactic cytokines. Of three disease-modifying drugs tested, dexamethasone and gold sodium thiomalate (GST) inhibited the production of IL-8 and MCP-1, while methotrexate (MTX) was inactive. Dexamethasone reduced the production of MCP-1 and IL-8 by 20-65% and 60-80%, respectively, whilst GST inhibited MCP-1 and IL-8 synthesis in suboptimally, but not in optimally stimulated synoviocytes. Taken together, these results show that the production of MCP-1 and IL-8 is similarly affected by anti-rheumatic drugs and that dexamethasone is the most potent inhibitor suggesting that part of the anti-rheumatic action of glucocorticoids is due to prevention of accumulation of chemotactic cytokines acting on neutrophils and monocytes.
Department of Rheumatology, University of Bern, Inselspital, Switzerland.
P
P
Loetscher
B
B
Dewald
M
M
Baggiolini
M
M
Seitz
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2; D002630:Chemotactic Factors / Q000032:analysis / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006052:Gold Sodium Thiomalate / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000032:analysis / Q000096:biosynthesis*; D007700:Kinetics; D008727:Methotrexate / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis; D011458:Prostaglandins E / Q000378:metabolism; D012680:Sensitivity and Specificity; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2; D002630:Chemotactic Factors; D016207:Cytokines; D007375:Interleukin-1; D016209:Interleukin-8; D011453:Prostaglandins; D011458:Prostaglandins E; D006052:Gold Sodium Thiomalate; D003907:Dexamethasone; D008727:Methotrexate