Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

Pancreatic beta cell damage caused by pro-inflammatory cytokines interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFN gamma-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1 beta, IFN gamma, TNF alpha. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFN gamma in beta cells. In summary, we show that interference with IFN gamma signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death.