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

Sarkar, Sagartirtha; Wong, Randall; Hackl, Seija I; Moua, Ong; Gill, Ronald G.; Wiseman, Alexander C.; Davidson, Howard W.; Hutton, John C.

doi:10.2337/db06-0617

Cited by 84 publications

(70 citation statements)

References 46 publications

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“…Hence, this enzyme is extremely sensitive to the depletion of P5P [200], and the upregulated TRYCAT pathway, in an environment of decreased P5P, leads to an increased availability of 3-HK for 3-HK-transaminase and subsequently increased production of xanthurenic acid and 8-HQ. This increases in the availability of kynurenine for KAT and thus increases the levels of KYNA and QA in the brain, blood, urine, and pancreatic islets [207][208][209][210]. Chronically elevated levels of these TRYCATs, notably xanthurenic acid, can have a number of deleterious effects on the production and function of insulin.…”

Section: Trycats and Scfas In Type 2 Diabetesmentioning

confidence: 99%

The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease

Morris¹,

et al. 2016

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There is a growing awareness that gut commensal metabolites play a major role in host physiology and indeed the pathophysiology of several illnesses. The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and hence, indirectly, the levels of serotonin in the brain. Some microbiota synthesize neurotransmitters directly, e.g., gamma-amino butyric acid, while modulating the synthesis of neurotransmitters, such as dopamine and norepinephrine, and brain-derived neurotropic factor (BDNF). The composition of the microbiota determines the levels and nature of tryptophan catabolites (TRYCATs) which in turn has profound effects on aryl hydrocarbon receptors, thereby influencing epithelial barrier integrity and the presence of an inflammatory or tolerogenic environment in the intestine and beyond. The composition of the microbiota also determines the levels and ratios of short chain fatty acids (SCFAs) such as butyrate and propionate. Butyrate is a key energy source for colonocytes. Dysbiosis leading to reduced levels of SCFAs, notably butyrate, therefore may have adverse effects on epithelial barrier integrity, energy homeostasis, and the T helper 17/regulatory/T cell balance. Moreover, dysbiosis leading to reduced butyrate levels may increase bacterial translocation into the systemic circulation. As examples, we describe the role of microbial metabolites in the pathophysiology of diabetes type 2 and autism.

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Section: Trycats and Scfas In Type 2 Diabetesmentioning

confidence: 99%

The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease

Morris¹,

et al. 2016

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“…The target genes of NF-κB as follows were upregulated by exposure of human islets to a combination of IL1β, TNF-α and IFN-γ: (1) cytokines/chemokines and their modulators (IL1α, IL1β, IL6, IL8, IP10, CXCL1, lymphotoxin β, MIP1α, MIP-2, RANTES, TNFα); (2) immunoreceptors (β2 microglobulin); (3) antigen presentation (TAP1); (4) cell adhesion (ICAM1); (5) acute-phase proteins (complement factor B, urokinasetype plasminogen activator, COX2); (6) cell surface receptors (LOX1); and (7) Cytokine combination: IL1β (2 ng/ml), TNF-α (10 ng/ml) and IFN-γ (10 ng/ml) a Genes that may play a protective role in islet survival and INF-γ alone [19] have been previously reported. This is the first report to show that exposure of cultured human islets to a combination of IL1β, TNF-α and IFNγ results in upregulation of several anti-apoptotic genes via NF-κB, namely BIRC3, BCL2A1, CFLAR, TNFAIP3 and TRAF1 (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…human serum albumin. Islets were exposed for 24 h to a mixture of IL1β (2 ng/ml; 100 U/ml), IFN-γ (10 ng/ml; 200 U/ml) and TNF-α (10 ng/ml; 1,000 U/ml) or IL1β (10 ng/ml; 500 U/ml), IFNγ (25 ng/ml; 500 U/ml) and TNFα (25 ng/ml; 2,500 U/ml) individually (Roche Applied Science, Indianapolis IN, USA) [18][19][20].…”

Section: Methodsmentioning

confidence: 99%

“…RNA isolation and microarray Total RNA extraction, purification and labelling were performed as described previously [19]. Using standard Affymetrix protocol (Affymetrix, Santa Clara, CA, USA), 15 µg of biotinlabelled cRNA was hybridised to Human genome HG U133 Plus 2.0 microarray chips (Affymetrix) containing 54,675 probe sets representing around 22,000 unique genes.…”

Section: Methodsmentioning

confidence: 99%

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Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line

et al. 2009

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Aims/hypothesis The destruction of pancreatic beta cells leading to type 1 diabetes in humans is thought to occur mainly through apoptosis and necrosis induced by activated macrophages and T cells, and in which secreted cytokines play a significant role. The transcription factor nuclear factor kappa-B (NF-κB) plays an important role in mediating the apoptotic action of cytokines in beta cells. We therefore sought to determine the changes in expression of genes modulated by NF-κB in human islets exposed to a combination of IL1β, TNF-α and IFN-γ. Methods Microarray and gene set enrichment analysis were performed to investigate the global response of gene expression and pathways modulated in cultured human islets exposed to cytokines. Validation of a panel of NF-κB-regulated genes was performed by quantitative RT-PCR. The mechanism of induction of BIRC3 by cytokines was examined by transient transfection of BIRC3 promoter constructs linked to a luciferase gene in MIN6 cells, a mouse beta cell line. Results Enrichment of several metabolic and signalling pathways was observed in cytokine-treated human islets. In addition to the upregulation of known pro-apoptotic genes, a number of anti-apoptotic genes including BIRC3, BCL2A1, TNFAIP3, CFLAR and TRAF1 were induced by cytokines through NF-κB. Significant synergy between the cytokines was observed in NF-κB-mediated induction of the promoter of BIRC3 in MIN6 cells. Conclusions/interpretation These findings suggest that, via NF-κB activation, cytokines induce a concurrent antiapoptotic pathway that may be critical for preserving islet integrity and viability during the progression of insulitis in type 1 diabetes.

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“…IFN-γ is not only a key factor in the pathogenesis of atherosclerosis [7], but also stimulates intracellular IDO activity in pancreatic islets, thereby increasing intracellular concentrations of kynurenines [55]. Results from early animal studies suggest that kynurenines are related to insulin resistance [44] and impaired β-cell function [46,56].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Kynurenines as predictors of acute coronary events in the Hordaland Health Study

Eussen

Ueland

Vollset

et al. 2015

International Journal of Cardiology

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

Cited by 84 publications

References 46 publications

The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease

The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease

Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line

Kynurenines as predictors of acute coronary events in the Hordaland Health Study

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