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Induction of Indoleamine 2,3-Dioxygenase by Interferon- in Human Islets

From the Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Heath Sciences Center, Aurora, Colorado

Address correspondence and reprint requests to John C. Hutton, Director of Research, Professor of Pediatrics, Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, 1775 Ursula St., Mail Stop B-140, Aurora, CO 80045-6511. E-mail: john.hutton{at}uchsc.edu

Abbreviations: HPRT, hypoxanthine phosphoribosyl transferase; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IRF-1, IFN- regulatory factor-1; IL, interleukin; JAK, janus kinase; KYN, kynurenine; MHC, major histocompatibility complex; 1-MT, 1--methyl Trp; PDX1, pancreatic duodenal homeobox 1; STAT, signal transducer and activator of transcription; Q-RTPCR, quantitative real-time PCR; TCA, trichloroacetic acid; TDO, Trp 2,3-dioxygenase; TNF-, tumor necrosis factor-; Trp, tryptophan; WARS, Trp-tRNA synthase

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial, rate-limiting step of tryptophan (Trp) catabolism along the kynurenine (KYN) pathway, and its induction in cells of the immune system in response to cytokines has been implicated in the regulation of antigen presentation and responses to cell-mediated immune attack. Microarray and quantitative PCR analyses of isolated human islets incubated with interferon (IFN)- for 24 h revealed increased expression of IDO mRNA (>139-fold) and Trp-tRNA synthase (WARS) (>17-fold) along with 975 other transcripts more than threefold, notably the downstream effectors janus kinase (JAK)2, signal transducer and activator of transcription (STAT)1, IFN- regulatory factor-1, and several chemokines (CXCL9/MIG, CXCL10/IP10, CXCL11/1-TAC, CCL2, and CCL5/RANTES) and their receptors. IDO protein expression was upregulated in IFN-–treated islets and accompanied by increased intracellular IDO enzyme activity and the release of KYN into the media. The response to IFN- was countered by interleukin-4 and 1-methyl Trp. Immunohistochemical localization showed IDO to be induced in cells of both endocrine, including pancreatic duodenal homeobox 1–positive ß-cells, and nonendocrine origin. We postulate that in the short term, IDO activation may protect islets from cytotoxic damage, although chronic exposure to various Trp metabolites could equally lead to ß-cell attrition.

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