Evidence that beta cell death in the nonobese diabetic mouse is Fas independent

Recent studies suggest that Pas expression on pancreatic beta cells may be important in the development of autoimmune diabetes in the nonobese diabeti c (NOD) mouse. To address this, pancreatic islets from NOD mice,cere analyz ed by flow cytometry to directly identify which cells express Pas and Pas l igand (FasL) ex vivo and after in vitro culture with cytokines, Pas express ion was not detected on beta cells isolated from young (35 days) NOD mice. In vitro, incubation of NOD mouse islets with both IL-1 and IFN-gamma was r equired to achieve sufficient Pas expression and sensitivity for islets to be susceptible to lysis by soluble Fast. In islets isolated from older (gre ater than or equal to 125 days) NOD mice, Pas expression was detected on a limited number of beta cells (1-5%). Past was not detected on beta cells fr om either NOD or Fas-deficient MRLlpr/lpr islets, Also, both NOD and MRLlpr /lpr islets were equally susceptible to cytokine-induced cell death, This e liminates the possibility that cytokine-treated murine islet cells commit " suicide" due to simultaneous expression of Pas and Fast. Last, we show that NO is not required for cytokine-induced Fas expression and Fas-mediated ap optosis of islet cells. These findings indicate that beta cells can be kill ed by Fas-dependent cytotoxicity; however, our results raise further doubts about the clinical significance of Pas-mediated beta cell destruction beca use few Fas-positive cells were isolated immediately before the development of diabetes.