Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74

被引：133

作者：

Heinrichs, Daniel ^{[2
]}

Knauel, Meike ^{[1
]}

Offermanns, Christian ^{[2
]}

Berres, Marie-Luise ^{[2
]}

Nellen, Andreas ^{[2
]}

Leng, Lin ^{[3
]}

Schmitz, Petra ^{[2
]}

Bucala, Richard ^{[3
]}

Trautwein, Christian ^{[2
]}

Weber, Christian ^{[4
]}

Bernhagen, Juergen ^{[1
]}

Wasmuth, Hermann E. ^{[2
]}

机构：

[1] Rheinisch Westfal TH Aachen Univ, Inst Biochem & Mol Cell Biol, D-52074 Aachen, Germany

[2] Rheinisch Westfal TH Aachen Univ, Dept Med 3, D-52074 Aachen, Germany

[3] Yale Univ, Sch Med, Dept Internal Med, Rheumatol Sect, New Haven, CT 06510 USA

[4] Univ Munich, Inst Cardiovasc Prevent, Munich, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 42期

基金：

美国国家卫生研究院;

关键词：

ACTIVATED PROTEIN-KINASE; HEPATIC STELLATE CELLS; RHEUMATOID-ARTHRITIS; CONCANAVALIN-A; CANCER CELLS; MICE; DISEASE; ATHEROSCLEROSIS; PROLIFERATION; ADIPONECTIN;

D O I：

10.1073/pnas.1107023108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine that has been implicated in various inflammatory diseases. Chronic inflammation is a mainstay of liver fibrosis, a leading cause of morbidity worldwide, but the role of MIF in liver scarring has not yet been elucidated. Here we have uncovered an unexpected antifibrotic role for MIF. Mice genetically deleted in Mif(Mif(-/-)) showed strongly increased fibrosis in two models of chronic liver injury. Pronounced liver fibrosis in Mif(-/)-mice was associated with alterations in fibrosis-relevant genes, but not by a changed intrahepatic immune cell infiltration. Next, a direct impact of MIF on hepatic stellate cells (HSC) was assessed in vitro. Although MIF alone had only marginal effects on HSCs, it markedly inhibited PDGF-induced migration and proliferation of these cells. The inhibitory effects of MIF were mediated by CD74, which we detected as the most abundant known MIF receptor on HSCs. MIF promoted the phosphorylation of AMP-activated protein kinase (AMPK) in a CD74-dependent manner and, in turn, inhibition of AMPK reversed the inhibition of PDGF-induced HSC activation by MIF. The pivotal role of CD74 in MIF-mediated antifibrotic properties was further supported by augmented liver scarring of Cd74(-/)-mice. Moreover, mice treated with recombinant MIF displayed a reduced fibrogenic response in vivo. In conclusion, we describe a previously unexplored antifibrotic function of MIF that is mediated by the CD74/AMPK signaling pathway in HSCs. The results imply MIF and CD74 as targets for treatment of liver diseases.

引用

页码：17444 / 17449

页数：6

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