Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells.
beta-cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for beta-cell apoptosis by studying the sensitivity of beta-cells from STAT-1 knockout (-/-) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1-/- mice were completely resistant to interferon (IFN)-gamma (studied in combination with interleukin [IL]-1beta)-mediated cell death (92 +/- 4% viable cells in STAT-1-/- mice vs. 56 +/- 3% viable cells in wild-type controls, P < or = 0.001) and had preserved insulin release after exposure to IL-1beta and IFN-gamma. Moreover, analysis of cell death in cytokine-exposed purified beta-cells confirmed that protection was due to absence of STAT-1 in the beta-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducible nitric oxide synthase transcription but did not interfere with monocyte chemoattractant protein 1 and macrophage inflammatory protein 3alpha expression. In vivo, STAT-1-/- mice were partially resistant to development of diabetes after multiple low-dose streptozotocin injections as reflected by mean blood glucose at 12 days after first injection (159 +/- 28 vs. 283 +/- 81 mg/dl in wild-type controls, P < or = 0.05) and diabetes incidence at the end of the follow-up period (39 vs. 73% in wild-type controls, P < or = 0.05). In conclusion, the present results indicate that STAT-1 is a crucial transcription factor in the process of IFN-gamma-mediated beta-cell death and the subsequent development of immune-mediated diabetes.
Gysemans
Conny A
CA
LEGENDO, UZ Gasthuisberg O&N, Herestraat 49, B-3000 Leuven, Belgium.
Ladrière
Laurence
L
Callewaert
Hanne
H
Rasschaert
Joanne
J
Flamez
Daisy
D
Levy
David E
DE
Matthys
Patrick
P
Eizirik
Décio L
DL
Mathieu
Chantal
C
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency / Q000502:physiology*
D016207:Cytokines; D004268:DNA-Binding Proteins; D007328:Insulin; D007375:Interleukin-1; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma