Evidence that beta cell death in the nonobese diabetic mouse is Fas independent. J Immunol 1999 Aug 01;163(3):1562-9
Date
07/22/1999Pubmed ID
10415060Scopus ID
2-s2.0-0033178741 (requires institutional sign-in at Scopus site) 108 CitationsAbstract
Recent studies suggest that Fas expression on pancreatic beta 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 beta cells isolated from young (35 days) NOD mice. In vitro, incubation of NOD mouse islets with both IL-1 and IFN-gamma 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 beta cells (1-5%). FasL was not detected on beta cells from either NOD or Fas-deficient MRLlpr/lpr islets. Also, both NOD and MRLlpr/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 beta cells can be killed by Fas-dependent cytotoxicity; however, our results raise further doubts about the clinical significance of Fas-mediated beta cell destruction because few Fas-positive cells were isolated immediately before the development of diabetes.
Author List
Thomas HE, Darwiche R, Corbett JA, Kay TWAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cell Death
Cells, Cultured
Cytokines
Diabetes Mellitus, Type 1
Fas Ligand Protein
Female
Islets of Langerhans
Ligands
Membrane Glycoproteins
Mice
Mice, Inbred MRL lpr
Mice, Inbred NOD
Nitric Oxide
Staining and Labeling
Up-Regulation
fas Receptor
