Cytokine signalling in the beta-cell: a dual role for IFNgamma.
IFNgamma (interferon gamma), a cytokine typically secreted by infiltrating immune cells in insulitis in Type 1 diabetes, is by itself not detrimental to beta-cells, but, together with other cytokines, such as IL-1beta (interleukin 1beta) and TNFalpha (tumour necrosis factor alpha), or dsRNA (double-stranded RNA), it induces beta-cell apoptosis. The complex gene and protein networks that are altered by the combination of cytokines clearly point towards synergisms between these agents. IFNgamma acts mostly via JAK (Janus kinase) activation, with the transcription factors STAT-1 (signal transducer and activator of transcription-1) and IRF-1 (IFNgamma regulatory factor-1) playing a central role in the downstream pathway. The study of mice with a disruption of these transcription factors has revealed a possible dual role for IFNgamma in beta-cell destruction by cytokines or dsRNA. We demonstrated that the absence of STAT-1 from beta-cells completely protects against IFNgamma+IL-1beta- and IFNgamma+dsRNA-mediated beta-cell death in vitro, whereas absence of IRF-1 does not prevent cytokine-induced beta-cell apoptosis. In vivo, a lack of the IRF-1 gene in pancreatic islets even promotes low-dose streptozotocin-induced diabetes, whereas lack of STAT-1 confers resistance against beta-cell death following low-dose streptozotocin-induced diabetes. Additionally, IRF-1(-/-) islets are more sensitive to PNF (primary islet non-function) after transplantation in spontaneously diabetic NOD (non-obese diabetic) mice, whereas STAT-1(-/-) islets are fully protected. Moreover, proteomic analysis of beta-cells exposed to IFNgamma or IFNgamma+IL-1beta confirms that very different pathways are activated by IFNgamma alone compared with the combination. We conclude that IFNgamma may play a dual role in immune-induced beta-cell destruction. Transcription factors drive this dual role, with STAT-1 driving beta-cell destruction and IRF-1 possibly playing a role in up-regulation of protective pathways induced by IFNgamma.
Gysemans
Conny
C
Laboratory of Experimental Medicine and Endocrinology (LEGENDO), UZ Gasthuisberg O&N, Katholieke Universiteit Leuven, Herestraat 49, bus 902, B-3000 Leuven, Belgium.
Callewaert
Hanne
H
Overbergh
Lutgart
L
Mathieu
Chantal
C
D000818:Animals; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D053612:Janus Kinases