Diabetes · 2007
Fas-associated death receptor signaling evoked by human amylin in islet beta-cells.
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Zhang Shaoping, Liu Hong, Yu Hua, Cooper Garth J S
Аннотация
OBJECTIVE: Aggregation of human amylin (hA) into beta-sheet-containing oligomers is linked to islet beta-cell dysfunction and the pathogenesis of type 2 diabetes. Here, we investigated possible contributions of Fas-associated death-receptor signaling to the mechanism of hA-evoked beta-cell apoptosis.
RESEARCH DESIGN AND METHODS: We measured responses to hA in isolated mouse islets and two insulinoma cell lines, wherein we measured Fas/Fas ligand (FasL) and Fas-associated death domain (FADD) expression by quantitative RT-PCR, Western blotting, and immunofluorescence staining. We used two anti-Fas/FasL blocking antibodies and the Fas/FasL antagonist Kp7-6 to probe roles of Fas interactions in the regulation of apoptosis in hA-treated beta-cells and measured Kp7-6-mediated effects on beta-sheet formation and aggregation using circular dichroism and thioflavin-T binding.
RESULTS: hA treatment stimulated Fas and FADD expression in beta-cells. Both blocking antibodies suppressed hA-evoked apoptosis but did not modify its aggregation. Therefore, Fas receptor interactions played a critical role in induction of this pathway. Interestingly, hA-evoked beta-cell apoptosis was suppressed and rescued by Kp7-6, which also impaired hA beta-sheet formation.
CONCLUSIONS: This is the first report linking hA-evoked induction and activation of Fas and FADD to beta-cell apoptosis. We have identified a Fas/FasL antagonist, Kp7-6, as a potent inhibitor of hA aggregation and related beta-cell death. These results also support an interaction between hA and Fas on the surface of apoptotic beta-cells. Increased expression and activation of Fas in beta-cells could constitute a molecular event common to the pathogenesis of both type 1 and type 2 diabetes, although the mode of pathway activation may differ between these common forms of diabetes.
RESEARCH DESIGN AND METHODS: We measured responses to hA in isolated mouse islets and two insulinoma cell lines, wherein we measured Fas/Fas ligand (FasL) and Fas-associated death domain (FADD) expression by quantitative RT-PCR, Western blotting, and immunofluorescence staining. We used two anti-Fas/FasL blocking antibodies and the Fas/FasL antagonist Kp7-6 to probe roles of Fas interactions in the regulation of apoptosis in hA-treated beta-cells and measured Kp7-6-mediated effects on beta-sheet formation and aggregation using circular dichroism and thioflavin-T binding.
RESULTS: hA treatment stimulated Fas and FADD expression in beta-cells. Both blocking antibodies suppressed hA-evoked apoptosis but did not modify its aggregation. Therefore, Fas receptor interactions played a critical role in induction of this pathway. Interestingly, hA-evoked beta-cell apoptosis was suppressed and rescued by Kp7-6, which also impaired hA beta-sheet formation.
CONCLUSIONS: This is the first report linking hA-evoked induction and activation of Fas and FADD to beta-cell apoptosis. We have identified a Fas/FasL antagonist, Kp7-6, as a potent inhibitor of hA aggregation and related beta-cell death. These results also support an interaction between hA and Fas on the surface of apoptotic beta-cells. Increased expression and activation of Fas in beta-cells could constitute a molecular event common to the pathogenesis of both type 1 and type 2 diabetes, although the mode of pathway activation may differ between these common forms of diabetes.