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Bansal, M.B. et al.

Bansal, Kovalovich, Gupta, Li, Agarwal, Radbill, Alvarez, Safadi, Fiel, Friedman, Taub,

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 CCl(4) 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.[1]

References

Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression. Bansal, M.B., Kovalovich, K., Gupta, R., Li, W., Agarwal, A., Radbill, B., Alvarez, C.E., Safadi, R., Fiel, M.I., Friedman, S.L., Taub, R.A. J. Hepatol. (2005) [Pubmed]

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