Opposite regulation of prostaglandin E2 synthesis by transforming growth factor-β1 and interleukin 10 in activated microglial cultures

We have recently shown that prostaglandin E-2 (PGE(2)) synthesis in activated microglia is tightly regulated by several substances (NO, neurotransmitters, pro-inflammatory cytokines), that might originate from intrinsic brain cells or from hematogenous cells infiltrating the brain in the course of inflammatory diseases. In view of the important immunoregulatory and neuroprotective functions recently attributed to PGE(2), in the present study we extended our analysis of factors regulating PGE, synthesis in rat microglial cultures to two anti-inflammatory and immunosuppressive cytokines, transforming growth factor beta 1 (TGF-beta 1) and interleukin 10 (IL-10), which share with PGE, the ability 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 synthesis is linked to that of PGE(2) by complex feed-back mechanisms. We found 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 showed an inhibitory effect. The two cytokines acted mainly by regulating the LPS-induced expression of the rate limiting enzymes of the two metabolic pathways, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS). Moreover, TGF-beta 1 counteracted the effect of the pro-inflammatory 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 the in vivo situation, they may provide a novel clue for understanding the specific role of TGF-beta 1 and IL-10 in several neurological diseases such as multiple sclerosis, in which their cerebral level was found to be elevated. (C) 1998 Elsevier Science B.V.