Z Gastroenterol 2015; 53 - A1_35
DOI: 10.1055/s-0034-1397076

MIF shows profibrotic properties after MCD diet via NKT cell population

D Heinrichs 1, M Knauel 1, ML Berres 2, P Fischer 2, C Trautwein 2, HE Wasmuth 2, J Bernhagen 1
  • 1RWTH Aachen University, Institute of Biochemistry and Molecular Cell Biology, Aachen, Germany
  • 2RWTH Aachen University, Medical Department III, Aachen, Germany

Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine. It has recently been recognized to function as a chemokine-like molecule in chronic inflammatory diseases. In a model of hepatotoxic liver injury, MIF shows anti-fibrotic properties via CD74 and AMPK. In a model of non-alcoholic steatohepatitis, MIF has anti-steatotic properties. Because NASH is also associated with fibrosis within the liver, we compared Mif -/- with wild-type mice in an experimental liver fibrosis and metabolic disease model.

Methods: Mif -/- and wild-type mice were fed a methionine- and choline deficient diet (MCD diet) for eight weeks. Fibrosis was analyzed by histology (Sirius red staining), hydroxyproline content and intrahepatic mRNA expression of fibrosis-related genes (Col1a1, Timp1, Tgfβ1 and Mmp2). Recruitment of immune cells, like T cells, NK cells, NKT cells was assessed by FACS analysis, while macrophages were quantified by immunohistochemical staining with F4/80. Expression of a cytokine profile which is associated with NKT cells was determined with quantitative RT-PCR.

Results: Constitutive Mif knockout mice (Mif -/-) showed decreased fibrosis after eight weeks of MCD diet as assessed by histology and hepatic collagen levels. Reduced liver fibrosis in Mif -/- mice was associated with strong alterations in fibrosis-relevant genes (Col1a1, Timp1, Mmp2 and Tgfβ1). The livers of Mif -/- mice showed less activated stellate cells compared to wild-type mice. Interestingly, FACS analysis revealed no major differences in immune cell infiltration between Mif -/- and wild-type mice, only the NKT population is strongly increased in Mif -/- mice. Cytokine profile analysis showed that NKT cells in livers of Mif -/- mice were skewed toward type II NKT cells.

Conclusions: In our metabolic NASH model MIF shows profibrotic effects which are probably mediated through type II NKT cells. These results describe a yet undiscovered relation of MIF and NKT cell subsets and are the basis for further evaluation of this chemokine in this liver disease model.

Corresponding author: Heinrichs, Daniel

E-Mail: dheinrichs@ukaachen.de