title: Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74.
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.
authors.affiliation: Medical Department III, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Heinrichs
authors.forename: Meike
authors.initials: M
authors.lastname: Knauel
authors.forename: Christian
authors.initials: C
authors.lastname: Offermanns
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Berres
authors.forename: Andreas
authors.initials: A
authors.lastname: Nellen
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Petra
authors.initials: P
authors.lastname: Schmitz
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.forename: Hermann E
authors.initials: HE
authors.lastname: Wasmuth
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000502:physiology*; D002251:Carbon Tetrachloride / Q000633:toxicity; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; C045084:invariant chain; D002251:Carbon Tetrachloride; D055372:AMP-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse