Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice

Background & Aims: The identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1 alpha and IL-1 beta in steatohepatitis remains elusive. Methods: We employed IL-1 alpha and IL-1 beta-deficient mice and transplanted marrow cells to study the role of liver-resident and bone marrow-derived IL-1 in steatosis and its progression to steatohepatitis. Results: Atherogenic diet-induced steatohepatitis in wild-type mice was associated with 16 and 4.6 fold-elevations in mRNA levels of hepatic IL-1 alpha and IL-1 beta, respectively. In mice deficient in either IL-1 alpha or IL-1 beta the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1 alpha-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1 alpha markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, and TNF alpha) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGF beta levels (p = 0.004). IL-1 alpha mRNA levels were two-folds lower in IL-1 beta-deficient mice, and IL-1 beta transcripts were three-folds lower in IL-1 alpha-deficient compared to wild-type mice. Hepatic cell derived IL-1 alpha rather than from recruited bone marrow-derived cells was required for steatohepatitis development. Conclusions: These data demonstrate the critical role of IL-1 alpha and IL-1 beta in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1 alpha and/or IL-1 beta to inhibit the development of steatohepatitis should be explored. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.