Contribution of Fas to diabetes development.
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 lpr(cg) or Fas(cg). Spontaneous diabetes was significantly delayed in NOD mice expressing Fas(cg), and the effect depended on the expression level of the transgene. However, Fas(cg)-bearing mice were still sensitive to diabetes transferred by splenocytes from overtly diabetic NOD mice. At the same time, Fas(cg) expression 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.
Savinov
Alexei Y
AY
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Tcherepanov
Andrew
A
Green
E Allison
EA
Flavell
Richard A
RA
Chervonsky
Alexander V
AV
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000473:pathology; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018375:Neutrophil Activation; D011506:Proteins / Q000502:physiology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D019014:fas Receptor / Q000502:physiology*
D011506:Proteins; D019014:fas Receptor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse