Lack of interleukin-1alpha or interleukin-1beta 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-1alpha and IL-1beta in steatohepatitis remains elusive. METHODS: We employed IL-1alpha and IL-1beta-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-1alpha and IL-1beta, respectively. In mice deficient in either IL-1alpha or IL-1beta the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1alpha-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1alpha markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, and TNFalpha) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFbeta levels (p = 0.004). IL-1alpha mRNA levels were two-folds lower in IL-1beta-deficient mice, and IL-1beta transcripts were three-folds lower in IL-1alpha-deficient compared to wild-type mice. Hepatic cell derived IL-1alpha rather than from recruited bone marrow-derived cells was required for steatohepatitis development. CONCLUSIONS: These data demonstrate the critical role of IL-1alpha and IL-1beta in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1alpha and/or IL-1beta to inhibit the development of steatohepatitis should be explored