Prostaglandin E₂ inhibits transforming growth factor β1-mediated induction of collagen α₁(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-β1 (TGF-β1)-mediated fibrogenesis is unknown. We assessed the impact of COX-2 inhibition and PGE₂ on the regulation of TGF-β1-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 PGE₂ on TGF-β1-mediated fibrogenesis was examined by measuring mRNA levels of collagen α1(I). PGE₂ receptor expression was analyzed by RT-PCR. Results Under basal conditions, NS398 suppressed PGE₂ synthesis and induced collagen α1(I) whereas exogenous PGE₂ suppressed expression of collagen α1(I). TGF-β1 induced COX-2 mRNA, COX-2 protein and PGE₂ biosynthesis. Importantly, TGF-β1-mediated induction of collagen α1(I) was markedly suppressed by the addition of exogenous PGE₂. All four major PGE₂ receptors were expressed in LX-1 cells. Conclusions These results suggest that COX-2-derived PGE₂ inhibits both basal and TGF-β1-mediated induction of collagen synthesis by HSC. Based on these findings, it will be important to determine whether inhibiting COX-derived PGE₂ synthesis alters the progression of liver fibrosis in vivo.