Fas is an apoptosis-inducing surface receptor involved in controlling tissue homeostasis and function at multiple sites. Here we show that β cells from the pancreata of newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients express Fas and show extensive apoptosis among those cells located in proximity to Fas ligand–expressing T lymphocytes infiltrating the IDDM islets. Normal human pancreatic β cells that do not constitutively express Fas, become strongly Fas positive after interleuken (IL)-1β exposure, and are then susceptible to Fas-mediated apoptosis. NG-monomethyl-l-arginine, an inhibitor of nitric oxide (NO) synthase, prevents IL-1β–induced Fas expression, whereas the NO donors sodium nitroprusside and nitric oxide releasing compound (NOC)-18, induce functional Fas expression in normal pancreatic β cells. These findings suggest that NO-mediated upregulation of Fas contributes to pancreatic β cell damage in IDDM.
Nitric Oxide Primes Pancreatic β Cells for Fas-mediated Destruction in Insulin-dependent Diabetes Mellitus
Address correspondence to Dr. Massimo Trucco, Children's Hospital of Pittsburgh, Rangos Research Center, 3705 Fifth Ave. at DeSoto St., Pittsburgh, PA 15213, Phone: 412-692-6570, FAX: 412-692-5809; Dr. Carla Giordano, Laboratory of Immunology, Division of Endocrinology, Istituto di Clinica Medica, Universita' di Palermo, Piazza dell Cliniche 2, 90127 Palermo, Italy, Phone: 39-91-655-2110, FAX: 39-91-655-2109; or Dr. Roberto Testi, Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”, Via Tor Vergata 135, 00133 Rome, Italy, Phone: 39-6-7259-6502, FAX: 39-6-7259-6505.
Dr. Stassi is personally indebted to GianDomenico Bompiani for his encouragement and support. The authors are also grateful to Dr. Susan Faas for her suggestions and constructive criticism, Read Fritsch who prepared the figures, and Patrick Hnidka who edited the manuscript.
The work was supported in part by National Institutes of Health grant DK46864 (M. Trucco) and CNR, Comitato Nazionale per le Biotecnologie e la Biologia Molecolare: Patologia Molecolare della malattia diabetica, 1996 (A. Galluzzo). R. De Maria is the recipient of an Associazione Italiana Ricerca sul Cancro fellowship.
Abbreviations used in this paper: APAAP, alkaline phosphatase antialkaline phosphatase; D-NMMA, NG-monomethyl-d-arginine; FasL, Fas ligand; IDDM, insulin-dependent diabetes mellitus; iNOS, inducible nitric oxide synthase; L-NMMA, NG-monomethyl-l-arginine; NHP, normal human pancreas; NO, nitric oxide; NOC, NO releasing compound; SNP, sodium nitroprusside; TUNEL, TdT-mediated dUTP-X nick end labeling.
Giorgio Stassi, Ruggero De Maria, Giuliana Trucco, William Rudert, Roberto Testi, Aldo Galluzzo, Carla Giordano, Massimo Trucco; Nitric Oxide Primes Pancreatic β Cells for Fas-mediated Destruction in Insulin-dependent Diabetes Mellitus . J Exp Med 20 October 1997; 186 (8): 1193–1200. doi: https://doi.org/10.1084/jem.186.8.1193
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