Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus.
Fas is an apoptosis-inducing surface receptor involved in controlling tissue homeostasis and function at multiple sites. Here we show that beta 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 beta cells that do not constitutively express Fas, become strongly Fas positive after interleuken (IL)-1beta exposure, and are then susceptible to Fas-mediated apoptosis. NG-monomethyl-L-arginine, an inhibitor of nitric oxide (NO) synthase, prevents IL-1beta-induced Fas expression, whereas the NO donors sodium nitroprusside and nitric oxide releasing compound (NOC)-18, induce functional Fas expression in normal pancreatic beta cells. These findings suggest that NO-mediated upregulation of Fas contributes to pancreatic beta cell damage in IDDM.
Stassi
G
G
Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, PA 15213, USA.
De Maria
R
R
Trucco
G
G
Rudert
W
W
Testi
R
R
Galluzzo
A
A
Giordano
C
C
Trucco
M
M
D000328:Adult; D017209:Apoptosis / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D009569:Nitric Oxide / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000473:pathology; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007375:Interleukin-1; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D009569:Nitric Oxide