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.

中文翻译：

---

肝细胞源性巨噬细胞迁移抑制因子介导小鼠和患者酒精性肝损伤

背景和目的 巨噬细胞迁移抑制因子 (MIF) 是一种多效细胞因子，有助于对损伤的炎症反应。MIF 由多种细胞类型表达；然而，MIF 在酒精性肝病 (ALD) 中的细胞来源和作用尚不清楚。在这里，我们测试了非髓细胞，特别是肝细胞，是 ALD 中 MIF 的重要细胞来源的假设。方法在 HuH7 和分化的 THP-1 细胞中测量 MIF 表达以响应乙醇。在 C57BL/6 (WT) 和 Mif-/- 骨髓嵌合体中评估了乙醇诱导的肝损伤。酒精性肝炎 (AH) 患者的外周和肝上血清中测量了 MIF，并通过肝脏活检中的免疫组织化学观察了 MIF。结果 HuH7 肝细胞，但不是 THP-1 巨噬细胞，释放 MIF 以响应培养物中的乙醇挑战。在非髓细胞中表达 MIF 的嵌合小鼠中（Mif-/-→WT），慢性乙醇喂养增加了 ALT/AST、肝脂肪变性和细胞因子/趋化因子 mRNA 的表达。相比之下，在非骨髓细胞中不表达 MIF 的嵌合小鼠 (WT→Mif-/-) 可免受乙醇诱导的肝损伤。AH 患者肝活检的免疫组织化学染色显示 MIF 主要定位于肝细胞。有趣的是，肝上血清（而非外周血清）中 MIF 的浓度与疾病严重程度的临床指标和 AH 患者死亡风险的增加呈正相关。结论 综合起来，这些数据提供的证据表明，肝细胞衍生的 MIF 在小鼠 ALD 的发病机制中至关重要，并且可能导致 AH 患者的肝损伤。总结：酒精性肝病是世界范围内可预防死亡的主要原因，并且缺乏特定的药物疗法。最近的研究已经认识到巨噬细胞迁移抑制因子 (MIF) 在对肝损伤的炎症反应中具有关键作用。然而，产生这种蛋白质的细胞仍然未知。我们目前的研究结果表明，肝细胞是肝脏中的主要细胞类型，主要负责响应酒精产生 MIF，从而促进肝损伤。我们的研究表明，抑制 MIF 产生的药物可能有益于治疗因过度饮酒而导致的肝病患者。