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.