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

Abstract

MIF, a multi-potent protein that exhibits both cytokine and chemotactic properties, is expressed by many cell types, including hepatocytes and non-parenchymal 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 mRNA was induced at both 4d and 25d of ethanol feeding. After chronic ethanol, hepatic triglycerides and plasma ALT and AST were increased in wild-type, but not MIF−/−, mice. In order to understand the role of MIF in chronic ethanol-induced liver injury, we investigated the early response of wild-type and MIF−/− to ethanol. Ethanol feeding for 4d increased apoptosis of hepatic macrophages and activated complement in both wild-type and MIF−/− mice. However, TNFα expression was increased only in wild-type mice. This attenuation of TNF-α expression was associated with fewer F4/80+ macrophages in liver of MIF−/− mice. After 25d of ethanol feeding, chemokine expression was increased in wild-type 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 wild-type, but not MIF−/−, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver. Conclusion 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.

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

“…Although one study has described MIF as an anti-fibrotic factor in a chemically induced liver fibrosis model 32 , MIF is a well-known mediator of liver inflammation and fibrosis, of BM cell recruitment to the liver and liver metastasis, and furthermore MIF tissue and plasma levels correlate with PDAC aggressiveness 33–37 . Here, we propose a novel role for exosomal MIF in PDAC liver metastasis and describe a mechanism through which MIF orchestrates this process.…”

Anti-apoptotic effects of phyllanthin against alcoholinduced liver cell death

“…After being activated, macrophage cells secrete a category of cytokines such as TNF-α, interleukin one beta and thus the activated macrophage cells are the main source of ROS in the liver [5,[29][30][31]. These inflammatory mediators lead to hepatocyte dysfunction, apoptosis and necrosis of hepatocytes, and the production of extracellular matrix proteins contributing to characteristic fibrosis [30,31].…”

“…These inflammatory mediators lead to hepatocyte dysfunction, apoptosis and necrosis of hepatocytes, and the production of extracellular matrix proteins contributing to characteristic fibrosis [30,31].…”

Immunity and inflammatory signaling in alcoholic liver disease

“…On the other hand, deficiency of the MCP-1 receptor, CCR2, exhibits alcohol-induced liver injury, suggesting that CCR2-mediated immune cell infiltration does not play a role in the pathogenesis of ALD [46]. Recent studies indicate an important role for macrophage migration inhibitor factor (MIF) in immune cell infiltration during ALD [47]. Using selective blockade of chemokines or chemokine receptors to understand the distinct effects on recruitment of immune cells and their possible development as therapeutic strategies in ALD is needed.…”