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Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis.

ABSTRACT: 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-/-, mice. In order to understand the role of MIF in chronic ethanol-induced liver injury, we investigated the early response of wildtype and MIF-/- to ethanol. Ethanol feeding for 4 days increased apoptosis of hepatic macrophages and activated complement in both wildtype and MIF-/- mice. However, tumor necrosis factor alpha (TNF-?) expression was increased only in wildtype mice. This attenuation of TNF-? expression was associated with fewer F4/80+ macrophages in liver of MIF-/- mice. After 25 days of ethanol feeding, chemokine expression was increased in wildtype mice, but not MIF-/- mice. Again, this protection was associated with decreased F4/80+ cells in MIF-/- mice after ethanol feeding. Chronic ethanol feeding also sensitized wildtype, but not MIF-/-, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver.Taken together, these data indicate that 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.

SUBMITTER: Barnes MA

PROVIDER: S-EPMC3597752 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis.

Barnes Mark A MA McMullen Megan R MR Roychowdhury Sanjoy S Pisano Sorana G SG Liu Xiuli X Stavitsky Abram B AB Bucala Richard R Nagy Laura E LE

Hepatology (Baltimore, Md.) 20130118 5

<h4>Unlabelled</h4>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 ...[more]

PMID: 23174952

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Project description:BACKGROUND & AIMS:Macrophage migration inhibitory factor (MIF) is a multi-potent cytokine that contributes to the inflammatory response to injury. MIF is expressed by multiple cell types; however, the cellular source and actions of MIF in alcoholic liver disease (ALD) are not well known. Here we tested the hypothesis that non-myeloid cells, specifically hepatocytes, are an important cellular source of MIF in ALD. METHODS:MIF expression was measured in HuH7 and differentiated THP-1 cells in response to ethanol. Ethanol-induced liver injury was assessed in C57BL/6 (WT) and Mif-/- bone marrow chimeras. MIF was measured in peripheral and suprahepatic serum, as well as visualized by immunohistochemistry in liver biopsies, from patients with alcoholic hepatitis (AH). RESULTS:HuH7 hepatocytes, but not THP-1 macrophages, released MIF in response to ethanol challenge in culture. In chimeric mice expressing MIF in non-myeloid cells (Mif-/-?WT), chronic ethanol feeding increased ALT/AST, hepatic steatosis, and expression of cytokine/chemokine mRNA. In contrast, chimeric mice not expressing MIF in non-myeloid cells (WT?Mif-/-) were protected from ethanol-induced liver injury. Immunohistochemical staining of liver biopsies from patients with AH revealed a predominant localization of MIF to hepatocytes. Interestingly, the concentration of MIF in suprahepatic serum, but not peripheral serum, was positively correlated with clinical indicators of disease severity and with an increased risk of mortality in patients with AH. CONCLUSIONS:Taken together, these data provide evidence that hepatocyte-derived MIF is critical in the pathogenesis of ALD in mice and likely contributes to liver injury in patients with AH. Lay summary: Alcoholic liver disease is a major cause of preventable mortality worldwide, and lacks specific pharmacological therapies. Recent studies have recognized that macrophage migration inhibitor factor (MIF) has a critical role in the inflammatory response to liver damage. However, the cells that produce this protein are still unknown. Our present findings reveal that hepatocytes, the main cell type in the liver, are primarily responsible for MIF production in response to alcohol, which promotes liver injury. Our study suggests that drugs inhibiting MIF production could be beneficial in treating patients with liver disease due to excessive alcohol consumption.

Dataset Information

Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis.

Publications

Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis.

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