Background 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-1α and IL-1β in steatohepatitis remains elusive. Aims & Methods We employed IL-1α and IL-1β-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 folds-elevations in mRNA levels of hepatic IL-1α and IL-1β, respectively. In mice deficient in either IL-1α or IL-1β the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1α-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1α markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, TNFα) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFβ (p=0.004). IL-1α mRNA levels were 2 folds lower in IL-1β-deficient mice, and IL-1β transcripts were 3 folds lower in IL-1α-deficient compared to wild-type mice. Hepatic cell derived IL-1α rather than from recruited bone marrow-derived cells is required for steatohepatitis development. Conclusions These data demonstrate the critical role of IL-1α and IL-1β in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1α and/or IL-1β to inhibit development of steatohepatitis should be explored.

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Abstract-To study the possible role of the human lipid-oxidizing enzyme 15-lipoxygenase (15-LO) in atherosclerosis, we overexpressed it specifically in the vascular wall of C57B6/SJL mice by using the murine preproendothelin-1 promoter. The mice overexpressing 15-LO were crossbred with low density lipoprotein (LDL) receptor-deficient mice to investigate atherogenesis. High levels of 15-LO were expressed in the atherosclerotic lesion in the double-transgenic mice as assessed by immunohistochemistry. The double-transgenic, 15-LO-overexpressing, LDL receptor-deficient mice (LDLR Ϫ/Ϫ /15LO) developed significantly larger atherosclerotic lesions at the aortic sinus compared with lesions in the LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice after 3 and 6 weeks (107 000 versus 28 000 m 2 [PϽ0.001] and 121 000 versus 87 000 m 2 [PϽ0.05], respectively) of an atherogenic diet. LDL from the LDLR Ϫ/Ϫ /15LO mice was more susceptible to oxidation than was the LDL from the control LDLR Ϫ/Ϫ mice, as shown by a shorter lag period for copper-induced conjugated diene formation. On the other hand, no differences were found in the levels of serum anti-oxidized LDL antibodies between the study groups. There were also no differences with respect to the density of macrophages and T lymphocytes infiltrating the lesions in both experimental groups. Taken together, these results support the hypothesis that 15-LO overexpression in the vessel wall is associated with enhanced atherogenesis.