Inhibition of indoleamine 2, 3-dioxygenase-mediated tryptophan catabolism accelerates crescentic glomerulonephritis

Abstract

Summary Immunomodulatory enzyme indoleamine 2, 3-dioxygenase (IDO) is one of the initial and rate-limiting enzymes involved in the catabolism of the essential amino acid tryptophan. Via catalysing tryptophan degradation, IDO suppresses adaptive T cell-mediated immunity and plays an important role in various forms of immune tolerance. Its role in T helper type 1 (Th1)-directed, cell-mediated crescentic glomerulonephritis (GN) is still unclear. Therefore, we investigated the activity and role of IDO in crescentic GN using a model of nephrotoxic serum nephritis (NTN), and IDO activity was inhibited by 1-methyl-tryptophan (1-MT) in vivo. Our results showed that activity of IDO, as determined by high performance liquid chromatography analysis of the kynurenine/tryptophan ratio, was increased markedly in the serum and renal tissue of NTN mice, and immunohistochemistry revealed that expression of IDO was up-regulated significantly in glomeruli and renal tubular epithelial cells during NTN. Treatment with 1-MT resulted in significantly exacerbated kidney disease with increased glomerular crescent formation, accumulation of CD4+T cells and macrophages in renal tissue, and augmented renal injury compared with phosphate-buffered saline-treated NTN mice, which was associated with enhanced Th1 responses and intrarenal cellular proliferation. These findings suggest that the development of NTN was regulated negatively by increased IDO activity, and IDO might play an important role in the pathogenesis of crescentic GN.