gamma-Interferon signaling in pancreatic beta-cells is persistent but can be terminated by overexpression of suppressor of cytokine signaling-1.
Proinflammatory cytokines, including gamma-interferon (IFN-gamma), have been implicated in the destruction of beta-cells in autoimmune diabetes. IFN-gamma signaling is transient in some cell types, but there is indirect evidence that it may be prolonged in beta-cells. In this study, we have shown that IFN-gamma signaling, measured by signal transducer and activator of transcription-1 (STAT1) activation and the expression of IFN-gamma-responsive genes, is persistent in beta-cells for as long as the cytokine is present. Because members of the suppressor of cytokine signaling (SOCS) family may regulate the duration of IFN-gamma signaling, their expression was investigated in beta-cells. We found that cytokine-inducible SH2-containing protein, SOCS-1, and SOCS-2 are expressed in primary islets and NIT-1 insulinoma cells, both at the mRNA and protein levels, after treatment with IFN-gamma and other proinflammatory cytokines. Transfected SOCS-1 was found to inhibit responses to IFN-gamma in NIT-1 insulinoma cells, including STAT1 activation, class I major histocompatibility complex upregulation, and IFN-gamma-induced cell death, but only when expressed at levels higher than those found in untransfected cells. Consistent with this, IFN-gamma signaling was not affected in SOCS-1-deficient beta-cells. Therefore, persistent IFN-gamma signaling in beta-cells is associated with SOCS-1 expression that is not sufficient to terminate signaling. Because overexpression of SOCS-1 can suppress responses to IFN-gamma, this may be a useful strategy for protecting beta-cells from cytotoxicity mediated by IFN-gamma and possibly other proinflammatory cytokines.
Chong
M M
MM
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Thomas
H E
HE
Kay
T W
TW
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D016923:Cell Death; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D015870:Gene Expression; D007340:Insulinoma / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism*; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D008156:Luciferases