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

2005; Elsevier BV; Volume: 42; Issue: 4 Linguagem: Inglês

10.1016/j.jhep.2004.11.043

1600-0641

Meena B. Bansal, Kellen Kovalovich, Ritu Gupta, Wei Li, Akansha Agarwal, Brian Radbill, Carlos E. Alvarez, Rifaat Safadi, Maria Isabel Fiel, Scott L. Friedman, Rebecca Taub,

Liver Disease and Transplantation

Background/AimsInterleukin-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.MethodsMMP-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.ResultsMMP-2 mRNA, protein, and activity was increased in IL-6−/− livers. Restoration of IL-6 signaling in IL-6−/− 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.ConclusionsIL-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. 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. 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. MMP-2 mRNA, protein, and activity was increased in IL-6−/− livers. Restoration of IL-6 signaling in IL-6−/− 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. 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.