Analysis of cytokine mRNA expression in pancreatic islets of nonobese diabetic mice.

Nonobese diabetic mice develop type 1 diabetes in an age-related and gender-dependent manner. Th1 (IFN-gamma and TNF-beta) and Th2 (IL-4 and IL-10) cytokine mRNA expression was analyzed in pancreatic islets isolated from female NOD mice with a high incidence of diabetes and male NOD mice with a low incidence of diabetes. The levels were measured at 5 time points from the onset of insulitis until the development of overt diabetes, using a semiquantitative reverse transcriptase PCR (RT-PCR) assay. IFN-gamma mRNA levels were significantly higher in the islets obtained from females than those of males, from 10 weeks of age. TNF-beta mRNA was expressed in both females and males between 5 and 15 weeks of age. However, TNF-beta mRNA levels were decreased in males at 20 weeks of age. In contrast, IL-4 mRNA levels were lower in females than in males. These results suggest that islet beta-cell destruction and diabetes in female NOD mice correlates with IFN-gamma and TNF-beta production in the islets, and that male NOD mice may be protected from autoimmune beta-cell destruction by down-regulation of these cytokines. Furthermore, our findings also suggest that insulitis and beta-cell destruction are independently regulated: TNF-beta is more important in forming and maintaining the insulitis, while IFN-gamma has a more important role in beta-cell destruction.