The role of Fas ligand in beta cell destruction in autoimmune diabetes of NOD mice.
Fas ligand (FasL), a type 2 membrane protein belonging to the TNF family, plays an important role in the induction of cell death. Ligation of Fas receptors by FasL results in apoptosis of the Fas-expressing cell. Autoimmune diabetes results from beta cell destruction by islet-reactive T cells, a process that involves beta cell apoptosis. This raises the question of whether the FasL-Fas pathway plays a major role in beta cell death. To address this issue it is important to know whether beta cells express Fas and/or FasL and, if so, whether induction of these molecules leads to beta cell death. In fact, both Fas and FasL have been demonstrated to be expressed by beta cells in response to cytokine stimulation, although there remains an argument in the literature as to whether beta cells truly express FasL. This is largely because FasL expression has only been demonstrable by immunohistochemistry and not by flow cytometry. Transgenic NOD mice with beta cells expressing a FasL transgene develop an accelerated form of diabetes. We show here that beta cells from FasL transgenic NOD mice are more susceptible to cytokine-induced apoptosis than wild-type beta cells, consistent with the hypothesis that if beta cells express FasL then Fas-FasL interaction on the beta cell surface is able to mediate beta cell self-death in the absence of T cells. Interventions that block the Fas-FasL pathway may be useful, therefore, in the prevention or treatment of type 1 diabetes.
Petrovsky
N
N
Autoimmunity Research Unit, Canberra Clinical School, University of Sydney, Canberra ACT 2606, Australia. nikolai.petrovsky@anu.edu.au
Silva
D
D
Socha
L
L
Slattery
R
R
Charlton
B
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015551:Autoimmunity / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology*; D053222:Fas Ligand Protein; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D013997:Time Factors; D019076:Transgenes / Q000235:genetics
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D007371:Interferon-gamma