TRANSFORMING GROWTH FACTOR-BETA(1) AUGMENTS MITOGEN-INDUCED PROSTAGLANDIN SYNTHESIS AND EXPRESSION OF THE TIS10 PROSTAGLANDIN SYNTHASE-2 GENE BOTH IN SWISS 3T3 CELLS AND IN MURINE EMBRYO FIBROBLASTS/

Transforming growth factor-beta (TGF-beta), a potent cytokine, modulat es a wide variety of biological responses. Among its actions, TGF-beta can augment prostaglandin synthesis in several cell types. Although T GF-beta alone has no effect on prostaglandin production in Swiss 3T3 c ells, we find that TGF-beta augments the ability of tetradecanoyl phor bol acetate (TPA) or serum to stimulate PGE, production. The TIS10 gen e is a primary response gene encoding a second form of prostaglandin s ynthase (PGS), the rate-limiting enzyme in the biosynthesis of prostag landins, thromboxanes, and prostacyclins from arachidonic acid. TIS10/ PGS-2 expression is induced by mitogens in Swiss 3T3 cells. TGF-beta a lso augments mitogen-induced synthesis and accumulation of TIS10/PGS-2 protein and induction of TIS10/PGS-2 message in Swiss 3T3 cells. In c ontrast, TGF-beta has little or no effect on the level of PGS-1 (EC1.1 4.99.1) message, either alone or in concert with TPA or serum. TGF-bet a concentrations in the range of 0.01-0.10 ng/ml (0.4-4.0 pM) maximall y enhance mitogen induction of TIS10/PGS-2 message. TPA-induced accumu lation of unspliced TIS10/PGS-2 transcript is augmented by TGF-beta, s uggesting that this cytokine exerts its effect on expression of the TI S10/PGS-2 gene by transcriptional regulation. TGF-beta also augments T PA-induced prostaglandin production, TIS10/PGS-2 antigen accumulation, and TIS10/PGS-2 message induction in primary cultures of mouse embryo fibroblasts. Dexamethasone attenuates TGF-beta enhancement of all the se mitogen-induced responses: PGE2 accumulation, appearance of TIS10/P GS-2 protein and message, and accumulation of TIS10/PGS-2 unprocessed transcript. (C) 1994 Wiley-Liss, Inc.