Role for macrophage migration inhibitory factor in peritoneal fibrosis

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MIF is known as a pro-inflammatory cytokine and recent studies have revealed multi-functional property of this cytokine in cell proliferation, fibrosis and angiogenesis. We investigated MIF' s role in PF by studying an experimental model of PF in MIF-knockout (MIF-/-) mice. Methods. PF was induced by intra-peritoneal infusion of chlorhexidine gluconate (CG) in wild type (WT) or MIF-/-mice from Balb/c origin. The mice were sacrificed at weeks 1-4 from the start of infusion and examined histologically. We also attempted to clarify whether an intraperitoneal injection of anti-MIF antibody could attenuate PF. The expression of MIF, TNF-α and the macrophage infiltration were examined by immunohistochemistry. Results. The peritoneum in WT showed progressive thickening by CG infusion. From week 2, peritoneal thickening was significantly inhibited in MIF-/-mice as compared with WT. The thickening was also inhibited by anti-MIF antibody treatment. Thickened peritoneum in WT showed massive infiltration of macrophages positive for F4/80 antigen. In MIF-/-mice, the infiltration is significantly inhibited. Ultrastructurally WT demonstrated mesothelial cells showing degenerative changes of the shape and sparse microvilli. In contrast, mesothelial cells in MIF-/-mice exhibited normal-shaped and extensive formation of thick microvilli. By immunohistochemical analysis, mesothelial cells and submesothelial compact zone in WT showed an increase in MIF expression at week 1. The expression further increased in the mesothelial layer supposed to be regenerated epithelium at week 3. TNF-α was strongly co-expressed with MIF in the mesothelium and compact zone in WT; however, the MIF-/- mice showed a significant decrease in TNF-α expression. Conclusions. Our data suggest that MIF plays important roles in PF. MIF inhibition may protect the progression of PF by the anti-inflammatory effect and also by the inhibition of mesothelial damage.