title: 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.
abstract: 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.
authors.affiliation: Department of Immunology, Parker Hughes Institute, 2720 Patton Road, St. Paul, MN 55113, USA. mcetkovic@ih.org
authors.forename: Marina
authors.initials: M
authors.lastname: Cetkovic-Cvrlje
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: 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
chemical_list: 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