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Cell Death in the Nonobese Diabetic Mouse Is Fas Independent1
*
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 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 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.
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