Cyclooxygenase-2 Promotes Hepatocellular Apoptosis by Interacting with TNF-α and IL-6 in the Pathogenesis of Nonalcoholic Steatohepatitis in Rats

Background and Purpose The underlying mechanisms of nonalcoholic steatohepatitis (NASH) are poorly understood, and little is known about hepatocellular apoptosis in NASH. Cyclooxygenase (COX)-2, the key enzyme in eicosanoid metabolism, is highly expressed in NASH. COX-2 can also regulate the release of mediators of inflammation, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. The aim of our study was to evaluate the effects of COX-2 on hepatocellular apoptosis and the mechanism of the action in the pathogenesis of NASH in rats. Methods Sprague-Dawley rats were fed a high-fat diet (HFD) or standard diet for 8 and 12 weeks. COX-2 and cytokines expression in hepatic tissue and TNF-alpha and IL-6 levels in serum were measured at 8 and 12 weeks. Moreover, celecoxib (10 mg/kg body weight once a day) was administered to rats for 4 weeks to inhibit the expression of COX-2. Liver pathology was assessed by hematoxylin and eosin (H&E) stain and electron microscopy. Hepatocyte apoptosis was evaluated by TUNEL staining. Results COX-2 messenger RNA and protein were highly expressed in livers of HFD rats and were correlated with the severity of steatohepatitis (R = 0.82, p < 0.01). COX-2 upregulation was preceded by increases in TNF-a and IL-6. The level of hepatocellular apoptosis was significantly higher in HFD rats than in the control rats. The hepatocellular apoptosis was suppressed by the inhibition of COX-2. Conclusions COX-2 may promote hepatocellular apoptosis by interacting with TNF-alpha and IL-6 in NASH in rats.