Z Gastroenterol 2011; 49 - V1_03
DOI: 10.1055/s-0030-1269517

MIF exerts anti-fibrotic effects in experimental liver fibrosis via CD74

D Heinrichs 1, M Jung 2, ML Berres 1, A Nellen 1, P Schmitz 1, R Bucala 3, C Trautwein 1, C Weber 4, J Bernhagen 2, HE Wasmuth 1
  • 1Medizinische Klinik III Universitätsklinikum Aachen, Aachen
  • 2Institut für Biochemie Universitätsklinikum Aachen, Aachen
  • 3Departement of Internal Medicine, New Haven, USA
  • 4Institut für Kardiovaskuläre Molekularbiologie, Universitätsklinikum Aachen, Aachen

Aims: Macrophage migration inhibitory factor (MIF) has been implicated in inflammatory diseases. Chronic inflammation is a mainstay of liver fibrosis but the specific role of MIF in liver scarring has not yet been elucidated. Here we uncover an unexpected anti-fibrotic role of MIF in vivo and in vitro. Methods: Liver fibrosis was induced by CCl4 and TAA in Mif‒/‒, Cd74‒/‒ mice and wild-type mice. Fibrosis was analyzed by histology (sirius red), hydroxyproline content and intrahepatic mRNA expression of fibrosis-related genes (Col1a1, Timp1, Tgfb1, Mmp2). In vitro, the effects of MIF on the proliferation and migration of platelet-derived growth factor (PDGF)-stimulated stellate cells were analyzed and the role of AMPK and CD74 was evaluated in the cell culture. Results: Constitutive MIF knockout mice (Mif‒/‒) showed strongly increased fibrosis in both models of chronic liver injury as assessed by histology, hepatic collagen levels and alterations in fibrosis-relevant genes (Col1a1, Timp1, Mmp2, Tgfb1). While Mif alone had no obvious effects on stellate cells, it strongly inhibited Pdgf-induced migration and proliferation of these cells. The inhibitory effects of Mif were mediated by Cd74, which is the most abundant MIF receptor on stellate cells. Recombinant Mif led to the phosphorylation of AMP-activated protein kinase (AMPK) in stellate cells. This mechanism was the basis for the inhibition of Pdgf-induced stellate cell activation by Mif, as shown by AMPK-specific blockade experiments. The crucial role of CD74 in MIF-mediated anti-fibrotic properties is further supported by augmented liver scarring in Cd74‒/‒ mice in vivo as assessed by histology and hepatic collagen content. Conclusions: We describe a novel and previously unexpected anti-fibrotic function of MIF which is mediated through CD74 and increased AMPK phosphorylation in stellate cells. These data imply MIF and its receptor CD74 as new targets for the treatment of fibrotic liver diseases.