To evaluate hepatoprotective effect of alpha-calcitonin gene-related peptide (alpha CGRP), we compared the susceptibilities of alpha CGRP-/-and wild-type mice to concanavalin A (Con A)-induced hepatitis. Twelve hours after Con A administration, serum transaminases were markedly higher in alpha CGRP-/- than wild-type mice, and much more extensive TUNEL-positive lesions and DNA fragmentation were detected in the livers of of alpha CGRP-/- mice. Notably, expression of IL-6 was selectively diminished in aCGRP-/- mice, suggesting that induction of IL-6 during acute inflammatory responses is blunted in alpha CGRP-/-mice. In addition, primary cultured alpha CGRP-/- hepatocytes were more susceptible to IFN-gamma-induced cell death than hepatocytes from wild-type mice. Administration of exogenous alpha CGRP reduced the incidence of apoptosis among hepatocytes and endothelial cells. It thus appears that aCGRP exerts a hepatoprotective effect by modulating cytokine expression and preventing apoptosis. (c) 2006 Elsevier Inc. All rights reserved.