Differential effects of interleukin-13 and interleukin-6 on Jak/STAT signaling and cell viability in pancreatic β-cells

Abstract

Pro-inflammatory cytokines are important mediators of β-cell demise in type 1 diabetes, and similar mechanisms are increasingly implicated in type 2 diabetes, where a state of chronic inflammation may persist. It is likely that the actions of anti-inflammatory cytokines are also altered in diabetes. Cytokines are released from immune cells, which may be recruited to the islets in diabetes, but they can also be produced by islet endocrine cells in response to environmental factors, including enteroviral infection. Since enteroviral infection of islet cells may influence the development of diabetes in humans, we examined the actions of two cytokines, IL-13 and IL-6, whose expression are reported to be altered in β-cells during enteroviral infection. Human and rodent islet cells were shown to express receptors for both IL-13 and IL-6, and treatment with either cytokine resulted in the rapid phosphorylation of STAT3 and STAT6. However, while β-cells were protected against a range of cytotoxic insults during exposure to IL-13, treatment with IL-6 enhanced cytotoxicity and western blotting revealed that IL-13 induced one specific isoform of phospho-STAT6 preferentially. Upon incubation with both cytokines together, the isoform of STAT6 that was upregulated by IL-13 alone was again induced, and the effects of IL-6 on β-cell viability were attenuated. Overall, the results suggest that induction of specific isoforms of STAT family transcription factors may underlie the cytoprotective actions of IL-13, and they imply that selective targeting of specific STAT-mediated signaling components could provide a means to ameliorate the loss of β-cell viability in diabetes.

Keywords: :

• Janus kinase
• STAT3
• STAT6
• interleukin-13
• interleukin-6
• pancreatic β-cells

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We wish to acknowledge, with thanks, the Oxford Centre for Islet Transplantation and the Worcestershire Clinical Research Unit for the provision of human islets. We thank Haima Raman for technical assistance funded by the Nuffield Foundation Bursary scheme. We also thank Dr Hannah Welters and Dr Sarah Richardson for helpful discussions during the preparation of this manuscript.

The work was supported by funding from the European Union’s Seventh Framework Programme PEVNET (FP7/2007-2013) under grant agreement number 261441.

Supplemental Material

Supplemental materials may be found here:

http://www.landesbioscience.com/journals/islets/article/24249