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Role of indoleamine 2,3-dioxygenase in pathology of the gastrointestinal tract.

ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) has the most important role in modulation of tryptophan-dependent effects in the gastrointestinal tract, including modulation of intestinal immune response. An increased IDO activity maintains immune tolerance and attenuates ongoing inflammation but allows immune escape and uncontrolled growth of gastrointestinal tumors. Accordingly, IDO represents a novel therapeutic target for the treatment of inflammatory and malignant diseases of the gastrointestinal tract. In this review article, we summarize current knowledge about molecular and cellular mechanisms that are involved in IDO-dependent effects. We provide a brief outline of experimental and clinical studies that increased our understanding of how enhanced IDO activity: controls host–microbiota interactions in the gut; regulates detrimental immune response in inflammatory disorders of the gastrointestinal system; and allows immune escape and uncontrolled growth of gastrointestinal tumors. Additionally, we present future perspectives regarding modulation of IDO activity in the gut as possible new therapeutic approaches for the treatment of inflammatory and malignant diseases of the gastrointestinal system.

SUBMITTER: Acovic A

PROVIDER: S-EPMC6295700 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Project description:Male meiotic germ cell including the spermatozoa represent a great challenge to the immune system, as they appear long after the establishment of normal immune tolerance mechanisms. The capacity of the testes to tolerate autoantigenic germ cells as well as survival of allogeneic organ engrafted in the testicular interstitium have led to consider the testis an immunologically privileged site. Disruption of this immune privilege following trauma, tumor, or autoimmune orchitis often results in male infertility. Strong evidence indicates that indoleamine 2,3-dioxygenase (IDO) has been implicated in fetal and allograft tolerance, tumor immune resistance, and regulation of autoimmune diseases. IDO and tryptophan 2,3-dioxygenase (TDO) catalyze the same rate-limiting step of tryptophan metabolism along a common pathway, which leads to tryptophan starvation and generation of catabolites collectively known as kynurenines. However, the relevance of tryptophan metabolism in testis pathophysiology has not yet been explored. Here we assessed the in vivo role of IDO/TDO in experimental autoimmune orchitis (EAO), a model of autoimmune testicular inflammation and immunologically impaired spermatogenesis. EAO was induced in adult Wistar rats with testicular homogenate and adjuvants. Control (C) rats injected with saline and adjuvants and normal untreated rats (N) were also studied. mRNA expression of IDO decreased in whole testes and in isolated Sertoli cells during EAO. TDO and IDO localization and level of expression in the testis were analyzed by immunostaining and Western blot. TDO is expressed in granulomas from EAO rats, and similar protein levels were observed in N, C, and EAO groups. IDO was detected in mononuclear and endothelial cells and reduced IDO expression was detected in EAO group compared to N and C rats. This phenomenon was concomitant with a significant reduction of IDO activity in EAO testis measured by tryptophan and kynurenine concentrations (HPLC). Finally, in vivo inhibition of IDO with 1-methyl-tryptophan increased severity of the disease, demonstrating down regulation of IDO-based tolerance when testicular immune regulation was disrupted. We present evidence that an IDO-based mechanism is involved in testicular immune privilege.

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Role of indoleamine 2,3-dioxygenase in pathology of the gastrointestinal tract.

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