Retinoic acid effects on endothelial cell function: interaction with interleukin 1.

Blood vessel angiogenesis is an important component of chronic synovitis, and its regulation may be mediated through local production and effects of certain inflammatory cytokines, including interleukin-1 (IL-1). Retinoic acid (RA) can alter the progression of some inflammatory arthritic diseases, presumably through effects on fibroblast collagenase and PGE2 production. To explore alternate hypotheses, we examined the interaction of retinoic acid and IL-1 on endothelial cell (EC) function and found that RA directly affects and modifies the effects of IL-1 on EC proliferation, prostacyclin production, and plasminogen activator inhibitor capacity (PAI-1). With respect to EC proliferation, cis- and trans-retinoic acid and retinol induced a dose-dependent increase of [3H]TdR uptake by cultured ECs, independent of the effects of serum or eicosanoid production. This effect was blocked by IL-1. With respect 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 was most marked at higher concentrations (20 U/ml) of IL-1. This effect was mediated through effects independent of cyclooxygenase (COX) production. With respect to plasminogen activator inhibitor capacity, both IL-1 and retinoic acid stimulated EC PAI-1 synthesis, but the individual 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 endothelium, described in this study, may play a role in the fashion through which retinoic acid alters the expression of synovitis in certain types of experimental inflammatory arthritis.