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pubmed:abstractText |
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.
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