Introduction: Liver fibrosis represents a wound healing response to chronic insults affecting both candidates for liver transplantation and transplanted patients. Interleukin-1Β (IL1Β) has been proposed as an important mediator of inflammation and tissue damage in acute and chronic liver disease. We aimed to determine whether the blockade of IL1Β signaling with interleukin-1 receptor antagonist (IL-1Ra) can modulate the progression from liver injury to fibrosis.

Methods: The contribution of IL-1Β and IL-1Ra was assessed in vitro using human hepatic stellate cells (hHSC) and in vivo in a mouse model of liver fibrosis induced by bile duct ligation (BDL). BDL was performed in wild type (WT), IL-1Ra knockouts (KO) and WT mice treated with rIL-1Ra. Hepatic fibrosis, expression of matrix metalloproteinases (MMP) and inflammation were quantified by RT-PCR at 1, 5, 15, and 32 days after BDL.

Results: hHSCs treated with IL-1Β showed an upregulation of IL-1Β, IL-1Ra and MMP-9 mRNA levels, that was prevented by addition of rIL-1Ra. WT and IL-1RaKO mice undergoing BDL showed a strong increase of IL-1Β, MMP-2, 9 and 13 in liver tissue and serum from base-line. Liver collagen and macrophage infiltration, and serum transaminases were significantly higher in IL-1RaKO mice when compared to WT mice. IL-1RaKO mice treated with exogenous rIL1-Ra showed a reduced liver fibrosis when compared to IL-1RaKO mice and that was similar to WT.

Conclusion: These data indicate a protective role for endogenous IL-1Ra during the progression of BDL-induced liver fibrosis in mice, and confirm the important contribution of IL-1Β mediating the progression from liver injury to fibrosis.

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