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Diabetes 50:2744-2751, 2001
© 2001 by the American Diabetes Association, Inc.

{gamma}-Interferon Signaling in Pancreatic ß-Cells Is Persistent but Can Be Terminated by Overexpression of Suppressor of Cytokine Signaling-1

Mark M.W. Chong, Helen E. Thomas, and Thomas W.H. Kay

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Proinflammatory cytokines, including {gamma}-interferon (IFN-{gamma}), have been implicated in the destruction of ß-cells in autoimmune diabetes. IFN-{gamma} signaling is transient in some cell types, but there is indirect evidence that it may be prolonged in ß-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 ß-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 ß-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 ß-cells. Therefore, persistent IFN-{gamma} signaling in ß-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 ß-cells from cytotoxicity mediated by IFN-{gamma} and possibly other proinflammatory cytokines.


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