OPPOSITE REGULATION OF PROSTAGLANDIN E-2 SYNTHESIS BY TRANSFORMING GROWTH-FACTOR-BETA-1 AND INTERLEUKIN-10 IN ACTIVATED MICROGLIAL CULTURES

We have recently shown that prostaglandin E-2 (PGE(2)) synthesis in ac tivated microglia is tightly regulated by several substances (NO, neur otransmitters, pro-inflammatory cytokines), that might originate from intrinsic brain cells or from hematogenous cells infiltrating the brai n in the course of inflammatory diseases. In view of the important imm unoregulatory and neuroprotective functions recently attributed to PGE (2), in the present study we extended our analysis of factors regulati ng PGE, synthesis in rat microglial cultures to two anti-inflammatory and immunosuppressive cytokines, transforming growth factor beta 1 (TG F-beta 1) and interleukin 10 (IL-10), which share with PGE, the abilit y to strongly deactivate peripheral macrophages and microglial cells. Moreover, we looked at the effect of the two cytokines on nitric oxide (NO) synthesis, another important microglial effector, whose synthesi s is linked to that of PGE(2) by complex feed-back mechanisms. We foun d that while both cytokines inhibited LPS-induced NO release, they had distinct and opposite regulatory activities on PGE(2) production. In fact, while TGF-beta 1 enhanced LPS-induced PGE(2) synthesis, IL-10 sh owed an inhibitory effect. The two cytokines acted mainly by regulatin g the LPS-induced expression of the rate limiting enzymes of the two m etabolic pathways, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS). Moreover, TGF-beta 1 counteracted the effect of the pro-inflam matory cytokine interferon-gamma, which in the same cultures has been shown to downregulate PGE(2) and to upregulate NO synthesis. Although the present in vitro observations cannot be directly extrapolated to t he in vivo situation, they may provide a novel clue for understanding the specific role of TGF-beta 1 and IL-10 in several neurological dise ases such as multiple sclerosis, in which their cerebral level was fou nd to be elevated. (C) 1998 Elsevier Science B.V.