γ-interferon signaling in pancreatic β-cells is persistent but can be terminated by overexpression of suppressor of cytokine signaling-1

Abstract

Proinflammatory cytokines, including γ-interferon (IFN-γ), have been implicated in the destruction of β-cells in autoimmune diabetes. IFN-γ signaling is transient in some cell types, but there is indirect evidence that it may be prolonged in β-cells. In this study, we have shown that IFN-γ signaling, measured by signal transducer and activator of transcription-1 (STAT1) activation and the expression of IFN-γ-responsive genes, is persistent in β-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-γ signaling, their expression was investigated in β-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-γ and other proinflammatory cytokines. Transfected SOCS-1 was found to inhibit responses to IFN-γ in NIT-1 insulinoma cells, including STAT1 activation, class I major histocompatibility complex upregulation, and IFN-γ-induced cell death, but only when expressed at levels higher than those found in untransfected cells. Consistent with this, IFN-γ signaling was not affected in SOCS-1-deficient β-cells. Therefore, persistent IFN-γ signaling in β-cells is associated with SOCS-1 expression that is not sufficient to terminate signaling. Because overexpression of SOCS-1 can suppress responses to IFN-γ, this may be a useful strategy for protecting β-cells from cytotoxicity mediated by IFN-γ and possibly other proinflammatory cytokines.