![]() ![]() IDO-mediated tryptophan catabolism results in depletion of tryptophan with concomitant generation of kynurenine and ultimately NAD (nicotinamide adenine dinucleotide). Furthermore, agents that inhibit IDO are under active investigation as potential adjuvants for tumor immunotherapy. Indeed, modulation of cellular IDO expression and/or activity is now increasingly implicated in inflammation and autoimmunity, organ transplantation and fetal rejection, and evasion of immune surveillance by tumor cells. Accordingly, an emerging immunological paradigm regards IDO as a key regulatory control enzyme in both innate and adaptive immune responses. These studies indicate that IDO-mediated tryptophan depletion in vitro results in inhibition of matrix-degrading metalloproteinase enzyme production, suppression of inflammatory responses, and promotion of immune tolerance. Recent studies have established an entirely novel important biological function for IDO. The expression of IDO in healthy tissues is generally quite low but is markedly upregulated in response to infection and inflammation. Tryptophan starvation enables the host to restrict the growth of intracellular pathogens. The ubiquitously expressed heme enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the non-hepatic oxidative degradation of tryptophan, the initial and rate-limiting step in tryptophan metabolism, resulting in depletion of this least abundant essential amino acid. However, these inflammatory events need to be balanced by the production of endogenous inhibitors, as inflammatory responses are generally localized and the consequent destruction of affected joints is less severe. These cytokines, by upregulation of several genes, are responsible both for the recruitment and continuous activation of the inflammatory cells and for inducing production of the enzymes that destroy bone and cartilage. Locally produced proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, and IL-6 play a pivotal role in the pathology of rheumatoid arthritis (RA). ![]() These findings suggest that IDO may play an important and novel role in the negative feedback of CIA and possibly in the pathogenesis of rheumatoid arthritis. Blocking IDO with 1-MT aggravated the severity of arthritis and enhanced the immune responses. ![]() The results demonstrated that development of CIA was associated with increased IDO activity and enhanced tryptophan catabolism in mice. Treatment with 1-MT resulted in an enhanced cellular and humoral immune response and a more dominant polarization to Th1 in mice with arthritis compared with vehicle-treated arthritic mice. Activity of IDO, as determined by measuring the levels of kynurenine/tryptophan ratio in the sera, was increased in the acute phase of arthritis and was higher in collagen-immunized mice that did not develop arthritis. The results showed significantly increased incidence and severity of CIA in mice treated with 1-MT. To assess the role of IDO in collagen-induced arthritis (CIA), a model of rheumatoid arthritis characterized by a primarily Th1-like immune response, activity of IDO was inhibited by 1-methyl-tryptophan (1-MT) in vivo. Induction of IDO by interferon-γ in macrophages and dendritic cells results in tryptophan depletion and suppresses the immune-mediated activation of fibroblasts and T, B, and natural killer cells. Recent studies suggest that modulation of tryptophan concentration via IDO plays a fundamental role in innate immune responses. In cultured cells, the induction of IDO leads to depletion of tryptophan and tryptophan starvation. Indoleamine 2,3-dioxygenase (IDO) is one of the initial and rate-limiting enzymes involved in the catabolism of the essential amino acid tryptophan. ![]()
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