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

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, USA.
Diabetes (Impact Factor: 8.1). 01/2007; 56(1):72-9. DOI: 10.2337/db06-0617
Source: PubMed


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)-gamma 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-gamma 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-gamma-treated islets and accompanied by increased intracellular IDO enzyme activity and the release of KYN into the media. The response to IFN-gamma was countered by interleukin-4 and 1alpha-methyl Trp. Immunohistochemical localization showed IDO to be induced in cells of both endocrine, including pancreatic duodenal homeobox 1-positive beta-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 beta-cell attrition.


Available from: Ronald Gill, Mar 18, 2016
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    • "Human islets were procured, processed, and cultured for 24 h in the absence or presence of recombinant human cytokines (interleukin [IL]-1β: 10 ng/mL [500 units/mL], interferon [IFN] γ: 25 ng/mL [500 units/mL], or tumor necrosis factor [TNF] α: 25 ng/mL [2,500 units/mL] or a cocktail mixture of IL-1β [2 ng/mL], IFNγ [10 ng/mL], and TNFα [10 ng/mL]), as described previously (24). Functionality of human islet preparations was assured by reversion of hyperglycemia following transplantation into streptozotocin-induced diabetic Rag2−/− B6 mice, as detailed elsewhere (24). "
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    Full-text · Article · Dec 2011 · Diabetes
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    • "Retinoic acid–receptor responder 3 (RARRES3) (8,9) was expressed in β-cells of fulminant type 1 diabetic pancreata (Supplementary Fig. 4). Cleaved caspase 8, a marker of the Fas-mediated extrinsic apoptotic pathway, cleaved caspase 9, a marker of the activated non–Fas-mediated apoptotic pathway, and activated caspases 3, a marker of the end stage of β-cell apoptosis, were expressed specifically in islet β-cells (Supplementary Fig. 4). "
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    Full-text · Article · Feb 2011 · Diabetes
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    • "MIG has also been shown to be important for protection from Trypanosoma cruzi infection in mice [24] and is associated with disease severity in human tuberculosis [25]. MIG is induced by IFN-γ and mediated via the JAK-STAT signalling pathway [26] and is therefore a marker of bioactive IFN-γ and functional JAK-STAT signalling. In CS stimulated PBMC there was a correlation between MIG and IFN-γ mRNA, although in the two volunteers with sterile protection there was more MIG relative to IFN-γ. "
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    Full-text · Article · Sep 2010 · PLoS ONE
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