Human and rodent pancreatic β-cells express IL-4 receptors and IL-4 protects against β-cell apoptosis by activation of the PI-3-Kinase and Jak/STAT pathways
Résumé
Secretion of pro-inflammatory cytokines is associated with loss of pancreatic β-cell viability and cell death. Interleukin-4 (IL-4) has been reported to mediate a protective effect against the loss of pancreatic β-cells and IL-4 receptors have been found in rat pancreatic β-cells at both the RNA and protein level. The aim of this study was to investigate IL-4 receptor expression on human islet cells and to examine the signalling pathways by which IL-4 exerts its effects using the rat β-cell lines, BRIN-BD11 and INS-1E. By means of immunohistochemistry, it was demonstrated that IL-4 receptors are present on human islet cells. Using a flow cytometric method for evaluating cell death, it was confirmed that incubating β-cells with IL-4 attenuated cell death induced by interleukin-1β and interferon-γ by approximately 65%. This effect was abrogated by the presence of the PI-3-kinase inhibitor, wortmannin, suggesting that activation of the PI-3-kinase pathway is involved. In support of this, Western blotting revealed that incubation of cells with IL-4 resulted in increased phosphorylation of Akt, a downstream target of PI-3-kinase. Increased tyrosine phosphorylation of STAT6 also occurred in response to IL-4 and a selective Jak3 inhibitor reduced the cytoprotective response. Both effects were prevented by over-expression of the tyrosine phosphatase, PTP-BL. We conclude that IL-4 receptors are functionally competent in pancreatic β-cells and that they signal via PI-3-kinase and Jak/STAT pathways. These findings may have implications for future therapeutic strategies for the management of diabetes.
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