Cyclooxygenase
-2 (COX-2) is upregulated in many cancers, and the prostanoids synthesized increase proliferation, improve angiogenesis, and inhibit apoptosis in several tissues. To explore the function of COX-2 in liver, transgenic (Tg) mice were generated containing a fusion gene (LIVhCOX-2) consisting of human COX-2 cDNA under the control of the human ApoE promoter. Six lines were developed; all of them expressed the LIVhCOX-2 transgene selectively in hepatocytes. The Tg mice exhibited a normal phenotype, and the increased levels of PGE 2 found were due to the constitutively expressed COX-2. Histological analysis of different tissues and macroscopic examination of the liver showed no differences between wild-type (Wt) and Tg animals. However, Tg animals were resistant to Fas-mediated liver injury, as demonstrated by low levels of plasmatic aminotransferases, a lesser caspase-3 activation, and Bax levels and an increase in Bcl-2, Mcl-1, and xIAP proteins, when compared with the Wt animals. Moreover, the resistance to Fas-mediated apoptosis is suppressed in the presence of COX-2-selective inhibitors, which prevented prostaglandin accumulation in the liver of Tg mice. Conclusion: These results demonstrate that expression of COX-2-dependent prostaglandins exerted a protection against liver apoptosis. (HEPATOLOGY 2007;45:631-638.)
C yclooxygenase-1 (COX-1) and COX-2 catalyze the first step in prostanoid biosynthesis. 1,2 COX-1 is constitutively expressed in many tissues and seems to be involved in the housekeeping function of prostaglandins (PGs), 3 whereas COX-2 is induced by a variety of stimuli such as growth factors, cytokines, hormones, and other cellular stresses. 1,4,5 Adult hepatocytes fail to induce COX-2 expression regardless of the pro-inflammatory factors used; only Kupffer, stellate, and immortalized mouse liver cells retain the ability to express COX-2. 6,7 In this regard, we demonstrated that fetal hepatocytes, which exhibit a liver phenotype distinct from the adult cells, were able to express COX-2 on stimulation with lipopolysaccharide and pro-inflammatory cytokines. 8 We also demonstrated that partial hepatectomy induced COX-2 in hepatocytes and contributed to the progression of cell cycle after partial hepatectomy. 9 Moreover, the high levels of CCAAT/enhancer binding protein-alpha (C/EBP-␣) in the adult liver, which binds to the NF-IL6 site and inhibits the activity of the COX-2 promoter, were responsible for the suppression of COX-2 inducibility in adult hepatocytes. 10 In addition to inflammation, COX-2 expression has been associated with carcinogenesis, angiogenesis, and tumor development. In liver, previous work has shown that COX-2 expression and prostaglandin (PG) synthesis are key components in the secretion of gelatinases (MMP-2 and MMP-9), adhesion and migration of hepatoma cells, and, therefore, in the remodeling of extracellular matrix that occurs under pathological circumstances such as tumor invasion. 11,12 In addition to liver regeneration after