HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Thomas, H. E. Articles by Kay, T. W. H. Search for Related Content PubMed PubMed Citation Articles by Thomas, H. E. Articles by Kay, T. W. H.

Evidence That Cell Death in the Nonobese Diabetic Mouse Is Fas Independent¹

Helen E. Thomas^*, Rima Darwiche^*, John A. Corbett and Thomas W. H. Kay^2,*

^* Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Victoria, Australia; and Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104

Recent studies suggest that Fas expression on pancreatic cells may be important in the development of autoimmune diabetes in the nonobese diabetic (NOD) mouse. To address this, pancreatic islets from NOD mice were analyzed by flow cytometry to directly identify which cells express Fas and Fas ligand (FasL) ex vivo and after in vitro culture with cytokines. Fas expression was not detected on cells isolated from young (35 days) NOD mice. In vitro, incubation of NOD mouse islets with both IL-1 and IFN- was required to achieve sufficient Fas expression and sensitivity for islets to be susceptible to lysis by soluble FasL. In islets isolated from older (125 days) NOD mice, Fas expression was detected on a limited number of cells (1–5%). FasL was not detected on cells from either NOD or Fas-deficient MRL^lpr/lpr islets. Also, both NOD and MRL^lpr/lpr islets were equally susceptible to cytokine-induced cell death. This eliminates the possibility that cytokine-treated murine islet cells commit "suicide" due to simultaneous expression of Fas and FasL. Last, we show that NO is not required for cytokine-induced Fas expression and Fas-mediated apoptosis of islet cells. These findings indicate that cells can be killed by Fas-dependent cytotoxicity; however, our results raise further doubts about the clinical significance of Fas-mediated cell destruction because few Fas-positive cells were isolated immediately before the development of diabetes.