Feedback control of the arachidonate cascade in rheumatoid synoviocytes by 15-deoxy-Δ12,14-prostaglandin J2

Rheumatoid arthritis (RA) is a chronic polyarticular joint disease associated with massive synovial proliferation, inflammation, and angiogenesis. PPAR-gamma ligands, both 15-deoxy-Delta (12'14)-prostaglandin J(2) (15d-PGJ(2)) and troglitazone (TRO), can inhibit the growth of RA synoviocytes in vitro, and suppress the chronic inflammation of adjuvant-induced arthritis in rats, but the potency of 15d-PGJ(2) is higher than TRO. Prostaglandin (PG) E-2 plays important roles in joint erosion and synovial inflammation. In the present study, 15d-PGJ(2), but not TRO and other prostanoids, suppressed interleukin (IL)-1 beta -induced PGE(2) synthesis in rheumatoid synovial fibroblasts (RSFs) through the inhibition of cyclooxygenase (COX-2) and cytosolic phospholipase A(2) (cPLA(2)) expression. Furthermore, the inhibition was not affected by pretreatment with anti-PPAR-gamma antibody. It means that this anti-inflammatory effect of 15d-PGJ(2) for PG synthesis may be independent of PPAR-gamma and 15d-PGJ(2) is a key regulator of negative feedback. of the arachidonate cascade on the COX pathway. These findings provide new insight into the feedback. mechanism of the arachidonate cascade. (C) 2001 Academic Press.