Signal Transducer and Activator of Transcription 6 (STAT6) as a Regulator of Pancreatic Beta Cell Health

Abstract

The incidence of type 1 diabetes (T1DM) is increasing annually and the disease pathophysiology remains to be completely understood. The current understanding suggests a complex interplay of genetic factors, environmental factors and the immune system that ultimately converge to cause selective destruction of the pancreatic beta cells. As part of this process immune cells (e.g. cytotoxic T-cells), infiltrate the islets and release pro-inflammatory cytokines (e.g. IL-1β, TNF-α and IFN-γ) which cause beta cell dysfunction and cell death. Increasing evidence suggests that there is an imbalance between the levels of pro-inflammatory and anti-inflammatory cytokines at the islet site in T1DM and this may contribute to beta cell death. Anti-inflammatory cytokines (e.g. IL-4, IL-13 and IL-10) are reported to be protective in certain animal models of the disease, but their roles in pancreatic beta cells have been less extensively studied. The work in this thesis primarily examines the pathway stimulated by the anti-inflammatory cytokines IL-13 and IL-4 and its role in mediating the cytoprotectivity in beta cells. Particularly, we examine whether STAT6 is central to these protective effects. It was confirmed that STAT6 plays a crucial role in IL-4 and IL-13 mediated protection of beta cells against a range of cytotoxic stimuli (pro-inflammatory cytokines, palmitate and serum withdrawal). Additionally, It was shown that IL-13 and IL-4 induce the upregulation of anti-apoptotic genes such as MCL1, BCLXL and SOCS1, in a STAT6 regulated manner in beta cells. Surprisingly, we observed the STAT6-dependent upregulation of a gene not previously associated with this pathway, SIRPα. This was further investigated as a regulator of beta cell viability and the results revealed that knockdown of SIRPα resulted in beta cell apoptosis, implicating this protein as a novel regulator of beta cell viability. Taken together, this work shows that loss of STAT6 renders beta cells vulnerable to cell death and suggest that therapeutic targeting of this pathway may offer a potential treatment for T1DM.