Contribution of Fas to diabetes development

• DOI: 10.1073/pnas.0237359100
• Publication Date: 2003-01-21T22:51:47Z
• Authors: Alexei Y. Savinov; Andrew Tcherepanov; E. Allison Green; Richard A. Flavell; Alexander V. Cher...
• Keywords: Antigens-CD95; 0301 basic medicine; 570; 0303 health sciences; Neutrophil-Activation; Animal; 610; Proteins; Apoptosis; Adoptive Transfer; Mice-Inbred-NOD; Neutrophil Activation; 3. Good health; Islets-of-Langerhans; Islets of Langerhans; Mice; 03 medical and health sciences; Diabetes Mellitus, Type 1; Mice, Inbred NOD; Receptor-Interacting Protein Serine-Threonine Kinases; SUPPORT-U-S-GOVT-P-H-S; Animals; fas Receptor; Diabetes-Mellitus-Insulin-Dependent; SUPPORT-NON-U-S-GOVT

Fas (Tnfrsf6, Apo-1, CD95) is a death receptor involved in apoptosis induced in many cell types. Fas have been shown to be expressed by insulin-producing beta cells in mice and humans. However, the importance of Fas in the development of autoimmune diabetes remains controversial. To further evaluate the importance of Fas in pathogenesis of diabetes, we generated NOD mice (nonobese diabetic mice developing spontaneous autoimmune diabetes) with beta cell-specific expression of a dominant-negative point mutation in a death domain of Fas, known as lprcgor Fascg. Spontaneous diabetes was significantly delayed in NOD mice expressing Fascg, and the effect depended on the expression level of the transgene. However, Fascg-bearing mice were still sensitive to diabetes transferred by splenocytes from overtly diabetic NOD mice. At the same time, Fascgexpression did neutralize the accelerating effect of transgenic Fas-ligand expressed by the same beta cells. Thus, both Fas-dependent and -independent mechanisms are involved in beta cell destruction, but interference with the Fas pathway early in disease development may retard or prevent diabetes progression.