Expression of macrophage migration inhibitory factor in human glomerulonephritis

Background. We have recently demonstrated that macrophage migration inhibit ory factor (MIF) plays a pathogenic role in experimental glomerulonephritis (GN). The aim of the current study was to investigate MIF expression in hu man GN. Methods. MIF expression was examined by in situ hybridization and immunohis tochemistry staining in 65 biopsies from a variety of glomerulonephridities . Results. There is constitutive expression of MIF mRNA and protein in normal human kidney that is largely restricted to tubular epithelial cells and to some glomerular epithelial cells. There was little change in the pattern o f MIF expression in nonproliferative forms of GN such as minimal change dis ease and membranous GN. However, there was a marked increase in both glomer ular and tubular MIF expression in proliferative forms of GN, including foc al segmental glomerulosclerosis (FGS), lupus nephritis, crescentic GN, and mesangiocapillary proliferative GN. The prominent macrophage and T-cell inf iltrate in these diseases were largely restricted to areas with marked up-r egulation of MIF expression, contributing to glomerular hypercellularity, g lomerular focal segmental lesions, crescent formation, tubulitis, and granu lomatous lesions. De novo MIF expression was evident in glomerular endothel ial cells and mesangial cells in proliferative forms of GN. In addition, ma ny infiltrating macrophages and T cells showed MIF mRNA and protein express ion. Quantitative analysis found that increased glomerular and tubular MIF expression gave a highly significant correlation with macrophage and T-cell accumulation, the severity of histologic lesions, and the loss of creatini ne clearance. Conclusions. Renal MIF expression is markedly up-regulated in proliferative forms of human GN, and this correlates with leukocyte infiltration, histol ogic damage, and renal function impairment. These results suggest that MIF may be an important mediator of renal injury in progressive forms of human GN. Based on these findings, together with the known pathogenic role of MIF in experimental GN, we propose that MIF is an attractive therapeutic targe t in the treatment of progressive forms of GN.