Prostaglandin E2 inhibits transforming growth factor beta 1-mediated induction of collagen alpha 1(I) in hepatic stellate cells

• Published in: Journal of hepatology 2004-08, Vol.41 (2), p.251-258
• Main Authors: Hui, Alex Y, Dannenberg, Andrew J, Sung, Joseph J Y, Subbaramaiah, Kotha, Du, Baoheng, Olinga, Peter, Friedman, Scott L
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Transformed; Collagen Type I - antagonists & inhibitors; Collagen Type I - biosynthesis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - biosynthesis; Dinoprostone - pharmacology; Dinoprostone - physiology; DNA-Binding Proteins - genetics; Heat-Shock Proteins - antagonists & inhibitors; Humans; Isoenzymes - biosynthesis; Isoenzymes - metabolism; Liver - cytology; Liver - drug effects; Liver - enzymology; Liver - metabolism; Membrane Proteins; Nitrobenzenes - pharmacology; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E - metabolism; RNA, Messenger - metabolism; Serpins; Smad Proteins; Sulfonamides - pharmacology; Trans-Activators - genetics; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta - physiology; Transforming Growth Factor beta1
• ISSN: 0168-8278

Cyclooxygenase-2 (COX-2) has been implicated in a number of hepatic stellate cell (HSC) functions but its relationship to transforming growth factor-beta 1 (TGF-beta 1)-mediated fibrogenesis is unknown. We assessed the impact of COX-2 inhibition and PGE(2) on the regulation of TGF-beta 1-stimulated matrix synthesis in an immortalized human HSC line, LX-1 and corroborated these findings in primary stellate cells. 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-beta 1-mediated fibrogenesis was examined by measuring mRNA levels of collagen alpha1(I). PGE(2) receptor expression was analyzed by RT-PCR. Under basal conditions, NS398 suppressed PGE(2) synthesis and induced collagen alpha 1(I) whereas exogenous PGE(2) suppressed expression of collagen alpha1(I). TGF-beta 1 induced COX-2 mRNA, COX-2 protein and PGE(2) biosynthesis. Importantly, TGF-beta 1-mediated induction of collagen alpha 1(I) was markedly suppressed by the addition of exogenous PGE(2). All four major PGE(2) receptors were expressed in LX-1 cells. These results suggest that COX-2-derived PGE(2) inhibits both basal and TGF-beta 1-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.