Macrophage migration inhibitory factor (MIF) acts as an anti-fibrotic cytokine in two distinct models of experimental liver fibrosis

D Heinrichs; M Jung; ML Berres; C Offermanns; P Schmitz; C Trautwein; J Bernhagen; HE Wasmuth

doi:10.1055/s-0030-1263832

Zeitschrift für Gastroenterologie, Table of Contents

Macrophage migration inhibitory factor (MIF) acts as an anti-fibrotic cytokine in two distinct models of experimental liver fibrosis

D Heinrichs ¹, M Jung ², ML Berres ¹, C Offermanns ¹, P Schmitz ¹, C Trautwein ¹, J Bernhagen ², HE Wasmuth ¹

¹RWTH Aachen, Medizinische Klinik III, Aachen, Germany
²RWTH Aachen, Institut für Biochemie und Molekularbiologie, Aachen, Germany

Abstract

Aims: Macrophage migration inhibitory factor (MIF) is a pleiotropic chemokine-like inflammatory cytokine which has been implicated in various chronic inflammatory diseases. Although a contribution of MIF is proposed during liver injury, its role during chronic liver injury and hepatic fibrogenesis has not yet been systematically investigated. Therefore, we compared MIF^–/– with wild-type mice in two independent models of experimental liver fibrosis.

Methods: Liver fibrosis was induced by injection of CCl₄ (6 weeks) or TAA (6 weeks) in MIF^–/– mice and wild-type mice. Fibrosis was assessed by staging of histology after sirius red staining and measurement of the intrahepatic hydroxyprolin content. Recruitment of immune cells (T cells, NK cells, NKT cells) to the liver was quantified by FACS analysis. The intrahepatic mRNA expression of fibrosis related genes (Collagen Ia1, TIMP-1, TGF-β, MMP-2, MMP-9, IL-10) was determined by quantitative RT-PCR. In vitro, migration (Boyden chamber) as well as proliferation (scratch assay) of the murine hepatic stellate cell line GRX was analyzed after stimulation with PDGF in the presence or absence of recombinant murine MIF.

Results: Unexpectedly, MIF^–/– mice displayed a significantly increased degree of fibrosis after treatment as assessed by liver histology and hydroxyproline content in both fibrosis models (all P <0.03). This increased liver fibrosis in MIF^–/– mice was associated with a significantly enhanced mRNA expression of fibrosis related genes (Collagen Ia1, TIMP-1, TGF-α, MMP-2, MMP-9; all P <0.05). Interestingly, FACS analysis revealed that the infiltration of immune cells to the liver was not altered after chronic injury between MIF^–/– and wild-type mice. However, recombinant MIF strongly inhibited the PDGF induced migration and proliferation of stellate cells in vitro (both P <0.01).

Conclusion: MIF exerts anti-fibrotic effects in two different models of toxic liver injury which seems to be mediated by a direct inhibitory effect on PDGF induced activation of hepatic stellate cells. These results describe a yet undiscovered anti-fibrotic property of MIF and are the basis for the further evaluation of this cytokine in liver diseases.