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Novel functions of B7-H4 in β cell physiology and stress response

University of British Columbia

Stress-induced failure and death of pancreatic β-cells are integral steps in the pathogenesis of type 1 and type 2 diabetes. Better understanding of the molecular interactions that influence β-cell function and stress signaling may therefore identify therapeutic targets to protect endogenous β-cells or transplanted islet grafts. B7-H4 is a negative co-stimulatory molecule that is expressed on the cell membranes of antigen presenting cells and down-regulates the immune response. Interestingly, pancreatic β-cells also express high levels of B7-H4 mRNA and moderate levels of B7-H4 protein. Of note, various tumor cells have up-regulated levels of B7-H4, which has been linked to metabolic and anti-apoptotic effects. This raises the intriguing possibility that B7-H4 may also regulate β-cell function, stress signaling, and survival independent of immune-regulation. In this study, we used mice with β-cell-specific overexpression of B7-H4, as well as B7-H4 knockout mice to examine the possible roles of B7-H4 in β-cell physiology and responses to endoplasmic reticulum (ER) stress. Cytosolic Ca²+ imaging showed that B7-H4 transgenic islets had increased sensitivity to sub-maximal glucose stimulation. Additional experiments indicated no differences in ER Ca²+ uptake/release or glucose metabolism, but revealed that B7-H4 transgenic islets are sensitized to tolbutamide and are resistant to diazoxide, suggesting changes at the ATP-sensitive potassium channels. The B7-H4-induced amplification of glucose-stimulated Ca²+ did not translate into detectable differences in in vitro insulin secretion or in vivo glucose tolerance, suggesting secondary control between rise in intracellular calcium and exocytosis of insulin granules. ER stress was induced in vitro using thapsigargin, and gene expressions were compared by real time quantitative PCR. Moderate ER stress induced the expression of key unfolded protein response genes, BiP, CHOP, and XBP1s to significantly higher levels in B7-H4 transgenic islets compared with wild type. However, the death of dispersed B7-H4 and wild type islet-cells did not differ following more severe and prolonged ER stress. Together, our findings demonstrate that over-expression of B7-H4 amplifies β-cell glucose-stimulated Ca²+ responses and the unfolded protein response during ER stress, revealing novel roles for B7-H4 in the pancreatic β-cell.

Text

2015-04-20

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/52872

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/