TNF-ALPHA UP-REGULATES RENAL MIF EXPRESSION IN RAT CRESCENTIC GLOMERULONEPHRITIS

Background: Macrophage migration inhibitory factor (MIF) is a potent p roinflammatory mediator that participates in the pathogenesis of endot oxemia and experimental crescentic glomerulonephritis. However, very l ittle is known about how MIF production is regulated in disease. We th erefore examined whether tumor necrosis factor alpha (TNF-alpha), a kn own inducer of MIF expression by macrophages in vitro, up-regulates lo cal and systemic MTF expression in a macrophage-mediated rat model of crescentic glomerulonephritis. Materials and Methods: Anti-glomerular basement membrane (GEM) glomerulonephritis was induced in groups of si x primed rats. Animals were treated with I mg/kg soluble TNF-alpha rec eptor (TNFbp) or saline from the time of disease induction until they were killed on Days 1, 7, or 14. Renal MIF expression was assessed by in situ hybridization, immunohistochemistry, and ELISA, and compared w ith macrophage accumulation and indices of renal damage. Results: Alth ough TNFbp treatment on Day 1 of the disease had only a partial effect upon the up-regulation of glomerular MIF expression, on Days 7 to 14 it almost completely abrogated the increase in glomerular and intersti tial MIF mRNA and protein expression. In addition, TNFbp treatment sig nificantly inhibited MIF secretion by cultured glomeruli and reduced s erum MIF levels. The inhibition of renal MIF expression was paralleled by a significant inhibition of glomerular and interstitial macrophage infiltration (p < 0.001 versus saline treated), a significant suppres sion of renal injury (proteinuria and serum creatinine), and a marked reduction in histologic damage (glomerular hypercellularity, crescent formation, and interstitial fibrosis; all p < 0.01 versus saline treat ed). Conclusions: This study demonstrates for the first time that TNF- alpha up-regulates local MIF expression by both infiltrating macrophag es and resident kidney cells in rat crescentic glomerulonephritis. In addition, TNF-alpha regulates systemic MIF production. Thus, TNF-alpha , together with MIF, may play a pathological role in immunologically i nduced renal disease.