SYNERGISTIC EFFECT OF INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA ON PGE(2) PRODUCTION BY ARTICULAR CHONDROCYTES DOES NOT INVOLVE PLA(2) STIMULATION

This study investigates the ways in which two proinflammatory cytokine s, tumor necrosis factor alpha (TNF) and interleulrin-1 beta (IL1), ca use increased production of prostaglandin E(2) (PGE(2)) in rabbit arti cular chondrocytes (RAC). Rabbit articular chondrocytes in primary cul ture were incubated with IL1, TNF, or both. Arachidonic acid (AA) rele ase, PGE(2) production, and the activities of cytosolic phospholipase A(2) (cPLA(2)), secreted phospholipase A(2) (sPLA(2)), and cyclooxygen ase (COX) were measured. The mRNA levels of cPLA(2), sPLA(2), and COX- 2 were also measured by Northern blotting, using specific complementar y DNA probes. Incubation of IL1-stimulated RAC with TNF further increa sed PGE(2) production. This synergy did not involve PLA(2) stimulation , as there were no increases in AA release, cPLA(2) and sPLA(2) activi ties, or mRNA. In contrast, TNF increased the effect of IL1 on COX-2 a ctivity and mRNA level, These results show that TNF and IL1 act in syn ergy in PGE(2) production in articular chondrocytes. As sPLA(2) and cP LA(2) do not seem to be involved, COX-2 appears to be the best target for a specific anti-inflammatory strategy against cartilage degradatio n. (C) 1996 Academic Press, Inc.