Interleukin-1 Receptor Antagonist Delays Progression of Liver Fibrosis

Abstract

Introduction: Liver fibrosis represents a wound healing response to chronic insults regardless of their mechanism. Ongoing inflammation triggers hepatic stellate cell activation that plays a central role in hepatic fibrogenesis. Kupffer cells have recently been involved in this activation cascade through their secretion of interleukin 1 beta (IL1B). Interleukin-1 receptor antagonist (IL1RA), an endogenous IL1B inhibitor, could represent a new strategy to prevent or delay inflammation during hepatic fibrosis. Our aim was to determine whether IL1RA can modulate progression from liver injury to fibrosis. Methods: We performed common bile duct ligation (BDL) on male DBA-1 wild type (WT) mice and on IL1RA knockouts (KO) mice in order to induce liver fibrosis. Following BDL, WT mice were treated with IL1RA (50 mg/kg/day), sham treated, or untreated. Liver samples were collected at days 0, 5, 15, and 32 following surgery. Collagen surface was quantified on multiple random microscopic sections using Masson trichrom staining and MetaMorph imaging software. Macrophages activation and aSMA expression were analyzed on tissue sections by immunohistochemistry. Expression of alpha-smooth muscle actin (aSMA), IL1RA, IL1B, collagen type I, Tissue Inhibitor of Matrix Metalloproteinase 1 (TIMP1), Matrix Metalloproteinase (MMP) 9 and 13 within the liver were assessed by RT-PCR. Results: We observed a shorter length of survival after BDL for IL1RA KO mice compared to wild type mice (9 vs 32 days median survival, p=0.03). WT mice treated with IL1RA showed similar survival compared to sham treated WT mice. Metamorph quantification of the fibrotic area ratio showed larger collagen deposits in IL1RA KO mice liver compared to WT mice. Moreover, WT mice treated with IL1RA tended to show less fibrotic area than sham treated WT mice. Immunohistochemistry showed higher aSMA levels and more macrophages activation in IL1RA KO mice when compared to WT mice. IL1RA, IL1B, and MMP9 transcription levels were lower in WT or WT mice treated with IL1RA compared to IL1RA KO mice. TIMP1 and collagen type I were non-significantly more expressed in IL1RAKO mice. MMP13 and aSMA levels were similar in the three groups. Conclusion: These data indicate a protective role for IL1RA and delays progression of liver fibrosis following common bile duct ligation in mice. They also support an important role of IL1B in the progression from liver injury to fibrosis.