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COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator

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Yu, J Ip, E dela Pena, A Hou, JY Sesha, J Hall, Peter [UCL] Leclercq, Isabelle [UCL] Farrell, GC

The underlying mechanisms that perpetuate liver inflammation in nonalcoholic steatohepatitis are poorly understood. We explored the hypothesis that cyclooxygenase-2 (COX-2) can exert pro-inflammatory effects in metabolic forms of fatty liver disease. Male wild-type (WT) C57BL6/N or peroxisome proliferator-activated receptor alpha knockout (PPAR-alpha(-/-)) mice were fed a lipogenic, methionine- and choline-deficient (MCD) diet or the same diet with supplementary methionine and choline (control). COX-2 was not expressed in livers of mice fed the control diet. In mice fed the MCD diet, hepatic expression of COX-2 messenger RNA and protein occurred from day 5, continued to rise, and was 10-fold higher than controls after 5 weeks, thereby paralleling die development of steatohepatitis. Upregulation of COX-2 was even more pronounced in PPAR-alpha(-/-) mice. Induction of COX-2 was completely prevented by dietary supplementation with the potent PPAR-alpha agonist Wy-14,643 in WT but not PPAR-alpha(-/-) mice. COX-2 upregulation was preceded by activation of nuclear factor kappa B (NF-kappa B) and coincided with increased levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and intercellular adhesion molecule 1 (ICAM-1). Selective COX-2 inhibitors (celecoxib and NS-398) protected against the development of steatohepatitis in WT but not PPAR-alpha(-/-) mice. In conclusion, induction of COX-2 occurs in association with NF-kappa B activation and upregulation of TNF-alpha, IL-6, and ICAM-1 in MCD diet-induced steatohepatitis. PPAR-alpha suppresses both COX-2 and development of steatohepatitis, while pharmacological inhibition of COX-2 activity ameliorates the severity of experimental steatohepatitis. COX-2 may therefore be a pro-inflammatory mediator in metabolic forms of steatohepatitis.

Document type Article de périodique (Journal article) – Article de recherche
Publication date 2006
Language Anglais
Journal information "Hepatology" - Vol. 43, no. 4, p. 826-836 (2006)
Peer reviewed yes
Publisher John Wiley & Sons Inc (Hoboken)
issn 0270-9139
e-issn 1527-3350
Publication status Publié
Affiliation UCL
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Bibliographic reference Yu, J ; Ip, E ; dela Pena, A ; Hou, JY ; Sesha, J ; et. al. COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator. In: Hepatology, Vol. 43, no. 4, p. 826-836 (2006)
Permanent URL http://hdl.handle.net/2078.1/38568