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Dual role of interferon-γ signalling pathway in sensitivity of pancreatic beta cells to immune destruction

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Title: Dual role of interferon-γ signalling pathway in sensitivity of pancreatic beta cells to immune destruction
Authors: Gysemans, Conny A, Pavlovic, D, Bouillon, R., Eizirik, Decio L., Mathieu, Cécile
Source: Diabetologia. 44:567-574
Publisher Information: Springer Science and Business Media LLC, 2001.
Publication Year: 2001
Subject Terms: 0301 basic medicine, Experimental -- surgery, Inbred Strains, Islets of Langerhans Transplantation, Nitric Oxide Synthase Type II, DNA-Binding Proteins -- physiology, Inbred C57BL, Phosphoproteins -- physiology, Mice, Phosphoproteins -- deficiency, Receptors, Nitric Oxide Synthase -- genetics, Receptors, Interferon, Mice, Knockout, 0303 health sciences, Phosphoproteins -- genetics, Reverse Transcriptase Polymerase Chain Reaction, Graft Survival, Interleukin-1 -- genetics, Sciences bio-médicales et agricoles, DNA-Binding Proteins, Interleukin-6 -- genetics, Experimental -- pathology, Homologous, DNA-Binding Proteins -- genetics, Knockout, Mice, Inbred Strains, Crosses, Diabetes Mellitus, Experimental, Interferon-gamma, Islets of Langerhans, 03 medical and health sciences, Genetic, Diabetes Mellitus, Animals, Interferon-gamma -- genetics, Interferon -- deficiency, Crosses, Genetic, Islets of Langerhans -- pathology, Transplantation, Interleukin-6, DNA-Binding Proteins -- deficiency, Experimental -- immunology, Phosphoproteins, Tumor Necrosis Factor-alpha -- genetics, Interferon -- physiology, Mice, Inbred C57BL, Islets of Langerhans -- immunology, Nitric Oxide Synthase, Interferon -- genetics, Interferon Regulatory Factor-1, Interleukin-1
Description: Disruption of the interferon-gamma (IFN-gamma) signalling pathway at the level of interferon regulatory factor-1 (IRF-1) protects islets against cytokine-induced nitric oxide production and cell death in vitro. The aim of this study was to investigate the effects of a global disruption of IFN-gamma signalling, or a selective disruption of IRF-1, on beta-cell sensitivity to in vivo immune destruction.In a first set of experiments, IFN-gamma receptor knockout mice (IFN-gammaR-/-) and interferon regulatory factor-1 knockout mice (IRF-1-/-) were rendered diabetic by injections of 50 mg streptozotocin i. p. on 5 consecutive days (MLDSTZ).Whereas no difference in sensitivity to MLDSTZ-induced diabetes could be observed between IFN-gammaR-/- mice and their 129/Sv/Ev controls (50% vs 55%, NS), there was an increased incidence of diabetes in IRF-1-/- mice (100% vs 67% in C57B1/6 mice, p < 0.05). A similar increased sensitivity to immune destruction of IRF-1-/- islets was observed when these islets were used as allografts. Islet graft survival rate of IFN-gammaR-/- and 129/Sv/Ev islets, when transplanted in alloxan-diabetic BALB/c recipients, was comparable (12.0 +/- 1.9 days vs 12.9 +/- 2.3 days, NS). Allograft rejection, however, of IRF-1-/- islets by BALB/c recipients occurred more rapidly than following transplantation to their C57B1/6 controls (9.1 +/- 2.0 days vs 13.1 +/- 1.5 days, p < 0.003).These data indicate that IFN-gamma signal transduction at the beta-cell level is not essential for immune beta-cell destruction in vivo. Moreover, disruption of the IRF-1 gene in pancreatic islets increases susceptibility to beta-cell killing, suggesting that IRF-1 might be necessary for the expression of putative beta-cell "defence and/or repair" genes.
Document Type: Article
File Description: No full-text files
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s001250051662
Access URL: https://link.springer.com/content/pdf/10.1007%2Fs001250051662.pdf
https://pubmed.ncbi.nlm.nih.gov/11380074
https://paperity.org/p/21983936/dual-role-of-interferon-g-signalling-pathway-in-sensitivity-of-pancreatic-beta-cells-to
https://difusion.ulb.ac.be/vufind/Record/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/52467/Details
https://www.ncbi.nlm.nih.gov/pubmed/11380074
https://rd.springer.com/article/10.1007/s001250051662
https://link.springer.com/content/pdf/10.1007%2Fs001250051662.pdf
https://europepmc.org/abstract/MED/11380074
Rights: Springer TDM
Accession Number: edsair.doi.dedup.....72fa40b05389b66a9be3da67bced2a8f
Database: OpenAIRE
Description
Abstract:Disruption of the interferon-gamma (IFN-gamma) signalling pathway at the level of interferon regulatory factor-1 (IRF-1) protects islets against cytokine-induced nitric oxide production and cell death in vitro. The aim of this study was to investigate the effects of a global disruption of IFN-gamma signalling, or a selective disruption of IRF-1, on beta-cell sensitivity to in vivo immune destruction.In a first set of experiments, IFN-gamma receptor knockout mice (IFN-gammaR-/-) and interferon regulatory factor-1 knockout mice (IRF-1-/-) were rendered diabetic by injections of 50 mg streptozotocin i. p. on 5 consecutive days (MLDSTZ).Whereas no difference in sensitivity to MLDSTZ-induced diabetes could be observed between IFN-gammaR-/- mice and their 129/Sv/Ev controls (50% vs 55%, NS), there was an increased incidence of diabetes in IRF-1-/- mice (100% vs 67% in C57B1/6 mice, p < 0.05). A similar increased sensitivity to immune destruction of IRF-1-/- islets was observed when these islets were used as allografts. Islet graft survival rate of IFN-gammaR-/- and 129/Sv/Ev islets, when transplanted in alloxan-diabetic BALB/c recipients, was comparable (12.0 +/- 1.9 days vs 12.9 +/- 2.3 days, NS). Allograft rejection, however, of IRF-1-/- islets by BALB/c recipients occurred more rapidly than following transplantation to their C57B1/6 controls (9.1 +/- 2.0 days vs 13.1 +/- 1.5 days, p < 0.003).These data indicate that IFN-gamma signal transduction at the beta-cell level is not essential for immune beta-cell destruction in vivo. Moreover, disruption of the IRF-1 gene in pancreatic islets increases susceptibility to beta-cell killing, suggesting that IRF-1 might be necessary for the expression of putative beta-cell "defence and/or repair" genes.
ISSN:14320428
0012186X
DOI:10.1007/s001250051662