RETINOIC ACID EFFECTS ON ENDOTHELIAL-CELL FUNCTION - INTERACTION WITHINTERLEUKIN-1(1)

Blood vessel angiogenesis is an important component of chronic synovit is, and its regulation may be mediated through local production and ef fects of certain inflammatory cytokines, including interleukin-1 (IL-1 ). Retinoic acid (RA) can alter the progression of some inflammatory a rthritic diseases, presumably through effects on fibroblast collagenas e and PGE(2) production. To explore alternate hypotheses, we examined the interaction of retinoic acid and IL-1 on endothelial cell (EC) fun ction and found that RA directly affects and modifies the effects of I L-1 on EC proliferation, prostacyclin production, and plasminogen acti vator inhibitor capacity (PAI-1). With respect to EC proliferation, ci s- and trans-retinoic acid and retinol induced a dose-dependent increa se of [H-3]TdR uptake by cultured ECs, independent of the effects of s erum or eicosanoid production. This effect was blocked by IL-1. With r espect to EC prostacyclin production, although retinoic acid alone had no effect, cis and trans-retinoic acid and retinol all induced a dose -dependent increase in IL-1-mediated prostacyclin production, which wa s most marked at higher concentrations (20 U/ml) of IL-1. This effect was mediated through effects independent of cyclooxygenase (COX) produ ction. With respect to plasminogen activator inhibitor capacity, both IL-1 and retinoic acid stimulated EC PAI-1 synthesis, but the individu al effects were additive, with RA augmenting the known IL-1 effects on EC PAI-1 production. The interaction between RA and IL-1 on the endot helium, described in this study, may play a role in the fashion throug h which retinoic acid alters the expression of synovitis in certain ty pes of experimental inflammatory arthritis. (C) 1994 Academic Press, I nc.