Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74
Open Access
- 3 October 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (42), 17444-17449
- https://doi.org/10.1073/pnas.1107023108
Abstract
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.This publication has 49 references indexed in Scilit:
- Impaired Macrophage Migration Inhibitory Factor–AMP-Activated Protein Kinase Activation and Ischemic Recovery in the Senescent HeartCirculation, 2010
- Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusionJCI Insight, 2009
- Antifibrotic Effects of CXCL9 and Its Receptor CXCR3 in Livers of Mice and HumansGastroenterology, 2009
- MIF Deficiency Reduces Chronic Inflammation in White Adipose Tissue and Impairs the Development of Insulin Resistance, Glucose Intolerance, and Associated Atherosclerotic DiseaseCirculation Research, 2009
- Hepatic stellate cells express functional CXCR4: Role in stromal cell-derived factor-1α-mediated stellate cell activationHepatology, 2009
- Structural determinants of MIF functions in CXCR2-mediated inflammatory and atherogenic leukocyte recruitmentProceedings of the National Academy of Sciences of the United States of America, 2008
- Mechanisms of Hepatic FibrogenesisGastroenterology, 2008
- Liver cirrhosisThe Lancet, 2008
- Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the LiverPhysiological Reviews, 2008
- The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tractNature, 1998