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

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

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

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 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. 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.

Original languageEnglish
Pages (from-to)548-556
Number of pages9
JournalJournal of Hepatology
Volume42
Issue number4
DOIs
StatePublished - Apr 2005

Keywords

  • Fibrosis
  • Interleukin-6
  • Liver injury
  • Matrix degradation
  • Matrix metalloproteinase-2
  • Stellate cells

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