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PMID: 21969590 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 108 ·No. 42 ·2011-10-18 ·Pages 17444-9

Heinrichs D, Knauel M, Offermanns C, Berres ML, Nellen A, Leng L, Schmitz P, Bucala R, Trautwein C, Weber C, Bernhagen J, Wasmuth HE

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.

MeSH Terms
AMP-Activated Protein Kinases/metabolism Animals Antigens, Differentiation, B-Lymphocyte/genetics,physiology Carbon Tetrachloride/toxicity Gene Expression Hepatic Stellate Cells/drug effects,pathology,physiology Histocompatibility Antigens Class II/genetics,physiology Intramolecular Oxidoreductases/deficiency,genetics,pharmacology,physiology Liver Cirrhosis, Experimental/drug therapy,etiology,pathology,physiopathology Macrophage Migration-Inhibitory Factors/deficiency,genetics,pharmacology,physiology Mice Mice, Inbred C57BL Mice, Knockout Platelet-Derived Growth Factor/pharmacology Recombinant Proteins/pharmacology Signal Transduction
Chemicals
Antigens, Differentiation, B-Lymphocyte Histocompatibility Antigens Class II Macrophage Migration-Inhibitory Factors Platelet-Derived Growth Factor Recombinant Proteins invariant chain Carbon Tetrachloride AMP-Activated Protein Kinases Intramolecular Oxidoreductases Mif protein, mouse
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Heinrichs Daniel
Medical Department III, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
Knauel Meike
Offermanns Christian
Berres Marie-Luise
Nellen Andreas
Leng Lin
Schmitz Petra
Bucala Richard
Trautwein Christian
Weber Christian
Bernhagen Jürgen
Wasmuth Hermann E
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1107023108
Published
2011-10-18
Epub
2011-00-03
Pages
17444-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3198363
Subset
IM
Grants
NIAMS NIH HHS · R01 AR050498 · United States
Corrections
CommentIn
PMID: 22461077
External Links
PubMed source DOI: 10.1073/pnas.1107023108 PMC Full Text View journal details
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