Macrophage Migration Inhibitory Factor Contributes to Ethanol-Induced Liver Injury by Mediating Cell Injury, Steatohepatitis, and Steatosis

Macrophage migration inhibitory factor (MIF), a multipotent protein that exhibits both cytokine and chemotactic properties, is expressed by many cell types, including hepatocytes and nonparenchymal cells. We hypothesized that MIF is a key contributor to liver injury after ethanol exposure. Female C57BL/6 or MIF-/-mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 (11% total kcal; early response) or 25 (32% kcal; chronic response) days. Expression of MIF messenger RNA (mRNA) was induced at both 4 days and 25 days of ethanol feeding. After chronic ethanol, hepatic triglycerides and plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased in wildtype, but not MIF-/-2, mice. In order to understand the role of MIF in chronic ethanol-induced liver injury, we investigated the early response of wildtype and MIF-/-2 to ethanol. Ethanol feeding for 4 days increased apoptosis of hepatic macrophages and activated complement in both wildtype and MIF-/-2 mice. However, tumor necrosis factor alpha (TNF-alpha) expression was increased only in wildtype mice. This attenuation of TNF-alpha expression was associated with fewer F4/801 macrophages in liver of MIF-/-2 mice. After 25 days of ethanol feeding, chemokine expression was increased in wildtype mice, but not MIF-/-2 mice. Again, this protection was associated with decreased F4/801 cells in MIF-/-2 mice after ethanol feeding. Chronic ethanol feeding also sensitized wildtype, but not MIF-/-2, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver. Conclusion: MIF is an important mediator in the regulation of chemokine production and immune cell infiltration in the liver during ethanol feeding and promotes ethanol-induced steatosis and hepatocyte damage. (HEPATOLOGY 2013;57:1980-1991)