IDO: A Novel Endogenous Suppressor of Inflammation

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DESCRIPTION (Taken from the applicant's abstract): Rheumatoid arthritis (RA) is characterized by chronic progressive synovial inflammation and subsequent destruction of articular structures. The pathogenesis of rheumatoid synovitis involves complex interaction between T lymphocytes, autonomously activated fibroblast-like synovial cells (FLS) and networks of inflammatory cytokines. Activation of FLS with increased expression of matrix metalloproteinases (MMP) and cyclooxygenase-2 (Cox-2) enzymes are key steps in pannus formation and tissue invasion, and contribute to that catalyzes the initial and rate-limiting step in the metabolism of the essential amino acid tryptophan (TRP. IDO causes depletion of available TRP, culminating in local TRP starvation in tissue, and reduced TRP concentration in serum. IDO expression is induced by interferon-y (IFN-y) in multiple cells, including FLS. IDO activity is elevated in RA and other chronic inflammatory states, but the true physiologic role of this enzyme remains unknown. Recent observations from our laboratory and other investigators indicate that TRP depletion catalyzed by IDO exerts profound effects on immune and inflammatory pathways. We therefore now propose that IDO functions as a novel endogenous suppressor of inflammation, and modulates the course of inflammatory arthritis. Here we will examine the role of IDO in inflammatory arthritis in three interrelated Specific Aims. In Specific Aim 1, we will establish the fundamental importance of IDO and TRP catabolism in suppression of MMP and PGE production in normal FLS by IFN-y, and determine if constitutive IDO activation confers resistance of transfected cells to inflammatory stimuli in vitro. The cellular mechanisms underlying IDO-mediated suppression of inflammatory responses will be investigated in Specific Aim 2. In Specific Aim 3, we will examine if inhibition of IDO function in vivo murine collagen-induced arthritis using a competitive IDO inhibitor modulated the course of experimental arthritis. The potential of IDO and TRP starvation to modulate both early and late steps in the synovial inflammatory response makes an approach to synovitis treatment based on TRP depletion particularly appealing.