Prostaglandin E-2 inhibits transforming growth factor beta 1-mediated induction of collagen alpha(1)(I) in hepatic stellate cells

Background/Aims: Cyclooxygenase-2 (COX-2) has been implicated in a number of hepatic stellate cell (HSC) functions but its relationship to transforming growth factor-beta1 (TGF-beta1)-mediated fibrogenesis is unknown. We assessed the impact of COX-2 inhibition and PGE(2) on the regulation of TGF-beta1-stimulated matrix synthesis in an immortalized human HSC line, LX-1 and corroborated these findings in primary stellate cells.Methods: Expression of COX-2 was assessed by Western blotting and real time quantitative PCR. The effect of NS398, a selective COX-2 inhibitor, and PGE(2) On TGF-beta1-mediated fibrogenesis was examined by measuring mRNA levels of collagen alpha1(I). PGE(2) receptor expression was analyzed by RT-PCR.Results: Under basal conditions, NS398 suppressed PGE(2) synthesis and induced collagen alpha1(l) whereas exogenous PGE(2) suppressed expression of collagen alpha1(I). TGF-beta1 induced COX-2 mRNA, COX-2 protein and PGE(2) biosynthesis. Importantly, TGF-beta1-mediated induction of collagen alpha1(l) was markedly suppressed by the addition of exogenous PGE(2). All four major PGE(2) receptors were expressed in LX-1 cells.Conclusions: These results suggest that COX-2-derived PGE(2) inhibits both basal and TGF-beta1-mediated induction of collagen synthesis by HSC. Based on these findings, it will be important to determine whether inhibiting COX-derived PGE(2) synthesis alters the progression of liver fibrosis in vivo. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.