Effect of targeted disruption of signal transducer and activator of transcription (Stat)4 and Stat6 genes on the autoimmune diabetes development induced by multiple low doses of streptozotocin.
The MLDS (multiple low doses of streptozotocin) model of diabetes was induced in Stat4(-/-), Stat6(-/-), and double-deficient Stat4(-/-)/6(-/-) mice to examine the role of STAT4/STAT6 deficiency in development of autoimmune diabetes. Cytokine production of T-cells from Stat4(-/-) mice confirmed a predominantly Th2-type immune response. Stat4(-/-) mice exhibited delayed onset and reduced severity of disease compared to wild-type (WT) mice. In contrast, STAT6 deficiency, with a predominant Th1 response, did not influence the kinetics or severity of MLDS-induced autoimmune diabetes. Interestingly, Stat4(-/-)/6(-/-) mice, with a prominent Th1-type response, experienced an accelerated and aggravated course of diabetes after MLDS, implicating a STAT4-independent Th1 response in the immunopathogenesis of MLDS-induced autoimmune diabetes. The sensitivity of islet cells from Stat4(-/-) or Stat4(-/-)/6(-/-) mice to cytokines and STZ was not different from that of islet cells of WT mice. Hence, the observed effects of STAT4 and STAT4/6 deficiency on MLDS-induced autoimmune diabetes are likely due to their effects on T-cell responses.
Cetkovic-Cvrlje
Marina
M
Department of Immunology, Parker Hughes Institute, 2720 Patton Road, St. Paul, MN 55113, USA. mcetkovic@ih.org
Uckun
Fatih M
FM
D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D002455:Cell Division; D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D013311:Streptozocin; D016176:T-Lymphocyte Subsets / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
D016207:Cytokines; D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D013311:Streptozocin