The role of macrophage migration inhibitory factor in autoimmune liver disease


  • Potential conflict of interest: Dr. Bucala is a coinventor on patent applications describing the utility of MIF genotype determination.

  • This work was supported by the National Institutes of Health (NIH; the clinical/translational, cell and molecular biology and morphology core facilities of P30 DK34989, the Yale Liver Center), an NIH Digestive Diseases Research Core Centers (DK034989-28) Liver Center Pilot Project Award (to D.A.), an American Liver Foundation Postdoctoral Autoimmune Hepatitis Grant (to D.A.), NIH T32 DK007356-33 (to D.A.), the German Research Foundation (DFG; BE1977/4-2 and SFB/TRR57-P07; to J.B.), NIH DK25636 (to J.L.B.), NIH AR050498 and AR049610 (to R.B.), and N01-HHSN272201100019C (to R.B.).


The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional −794 CATT5-8 microsatellite repeat (rs5844572) and a −173 G/C single-nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high-expression −794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme-linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls. Conclusions: These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases. (Hepatology 2014;59:580–591)