Celecoxib abrogates concanavalin A-induced hepatitis in mice: Possible involvement of Nrf2/HO-1, JNK signaling pathways and COX-2 expression

Concanavalin A (ConA) is an established model for inducing autoimmune hepatitis (AIH) in mice, mimicking clinical features in human. The aim of the current study is to explore the possible protective effect of celecoxib, a cyclooxygenase-2 inhibitor, on immunological responses elicited in the ConA model of acute hepatitis. ConA (20 mg/kg) was administered intravenously to adult male mice for 6 h. Prior to ConA intoxication, mice in the treated groups received daily doses of celecoxib (30 and 60 mg/kg in CMC) for 7 days. Results revealed that administration of celecoxib 60 mg/kg for 7 days significantly protected the liver from ConA-induced liver damage revealed by significant decrease in ALT and AST serum levels. Celecoxib 30 and 60 mg/kg pretreatment enhanced oxidant/antioxidant hemostasis by significant reduction of MDA and NO content and increase hepatic GSH contents and SOD activity. In addition, celecoxib 30 and 60 mg/kg caused significant increase in hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) and the stress protein heme oxygenase-1 (HO-1) levels. Moreover, celecoxib 30 and 60 mg/kg inhibited the release of proinflammatory markers including IL-1 & beta; and TNF-& alpha; along with significant decrease in p-JNK, AKT phosphorylation ratio and caspase-3 expression. Besides, Con A was correlated to high expression of cyclooxygenase COX-2 and this increasing was improved by administration of celecoxib. These changes were in good agreement with improvement in histological deterioration. The protective effect of celecoxib was also associated with significant reduction of autophagy biomarkers (Beclin-1 and LC3II).In conclusion, celecoxib showed antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagy activity against Con A-induced immune-mediated hepatitis. These effects could be produced by modulation of Nrf2/HO1, IL-1B /p-JNK/p-AKT, JNK/caspase-3, and Beclin-1/LC3II signaling pathways.

Automated summary

This study aimed to explore the possible protective effect of celecoxib, a cyclooxygenase-2 inhibitor, on immunological responses elicited in a mouse model of autoimmune hepatitis. Results showed that celecoxib significantly protected the liver from ConA-induced damage, improved antioxidant capacity, and inhibited inflammation and apoptosis. Moreover, celecoxib modulated multiple signaling pathways, leading to liver protection.