16, 17 Heinrichs et al. demonstrated that MIF causes an increase in AMPK phosphorylation in vitro, although this effect is weaker than

that of metformin. Thus, these findings indicate that the antifibrotic function of MIF in the liver might be mediated by the CD74/AMPK pathway in HSCs, whereas the proinflammatory action of MIF has been attributed to leukocyte recruitment processes via MIF/CXCR2 or MIF/CXCR4 in atherogenic, arthritic, and other murine models of inflammation.18, 19 The beneficial antifibrotic effect of MIF in a mouse model of liver fibrosis demonstrated in this study by Heinrichs et al.10 suggests that MIF is a novel target for treatment of chronic liver disease. Concomitant treatment of WT mice with recombinant MIF (rMIF) and CCl4 resulted in the attenuation of both HSC activation and the expression of fibrosis-associated genes. These therapeutic effects of MIF based on activating AMPK, which has a proven Selleckchem Panobinostat beneficial action on liver glucose and lipid metabolism,17 may have

an additional rationale in their antifibrogenic properties. Regarding the experimental approaches performed by Heinrichs et al., some questions still need to be answered. Because the authors investigated the role of MIF in two models of liver fibrosis using Mif−/− mice, investigating whether the expression of Mif in WT mice was altered when treated with TAA or CCl4 would be crucial to our understanding; a decrease in the expression of Mif would support the subsequent results of this BMN 673 manufacturer study. In addition, the phosphorylation of AMPK was shown to be induced by rMIF in HSCs isolated from untreated Mif−/− mice; thus, the activation status of AMPK should be determined in HSCs isolated DOK2 from the liver of TAA- or CCl4-treated Mif−/− mice. With regard to the in vitro experiments in which MIF inhibited PDGF-induced HSC migration and proliferation via the CD74/AMPK pathway, it is not clear why MIF alone did not modify these functions of HSCs, given that primary HSCs from Mif-deficient mice were used. The authors speculate that these MIF-mediated effects only occur under energy-consuming conditions. In fact,

it was reported that a common polymorphism in the human MIF promoter containing 5, 6, 7, or 8 CATT tetra-nucleotide repeat units has functional differences with respect to MIF secretion and cellular AMPK activation; furthermore, human fibroblasts with the “5 CATT” polymorphism exhibit diminished MIF release and AMPK activation during hypoxia.20 It would be appropriate to investigate further the presence of this polymorphism in the immortalized murine HSCs used in this study and to determine the subsequent effects of this polymorphism, if any. In conclusion, this study sheds light upon the novel mechanism of MIF signaling in liver fibrosis. MIF, which is believed to be a pleiotropic inflammatory cytokine, was shown for the first time to have antifibrotic properties in the liver.