Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression

Background/Aims: Interleukin-6 stimulates liver regeneration and promotes hepatoprotection following experimental liver injury, but underlying mechanisms have not been fully characterized. Because studies suggest matrix metalloproteinase-2 (MMP-2) may promote liver injury, we examined whether IL-6 exerted its protective effects via regulation of MMP-2. Methods: MMP-2 was analyzed in livers of IL-6-/- and IL-6+/+ mice following CCl4 administration. IL-6-/- mice were pretreated with IL-6 and liver histology and MMP-2 expression were examined after liver injury. IL-6-/- mice were treated with an MMP-2 inhibitor and assessment of injury (histology and serum ALT levels), apoptosis by TUNEL assay, and hepatocyte proliferation by BRDU-labeling was performed. These studies were complemented by analysis of cultured stellate cells. Results: MMP-2 mRNA, protein, and activity was increased in IL-6-/- livers. Restoration of IL-6 signaling in IL6-/- mice rescued injury and restored MMP-2 expression to wild-type levels. Furthermore, pharmacologic inhibition of MMP-2 decreased hepatocellular injury and apoptosis in IL-6-/- mice. In cultured stellate cells, recombinant IL-6 suppressed endogenous MMP-2 mRNA and protein expression. Conclusions: IL-6 may be hepatoprotective in acute injury through down-regulation of MMP-2. These findings suggest a role for MMP-2 in amplifying liver injury in vivo. (C) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.