LOCAL PRODUCTION OF HUMAN IL-6 PROMOTES INSULITIS BUT RETARDS THE ONSET OF INSULIN-DEPENDENT DIABETES-MELLITUS IN NONOBESE DIABETIC MICE

We produced transgenic mice which overexpress human IL-6 in pancreatic beta cells of C57BL/6 x CBA and non-obese diabetic (NOD) mice. Transg enic C57BL/6 x CBA mice back-crossed onto a C57BL/6 background do not develop insulitis or diabetes. In contrast, NOD/F-1 transgenic mice de velop a lymphocytic infiltrate of pancreatic islets which is not seen in negative littermates, Immunohistochemistry reveals these cells to b e predominantly CD4(+), CD8(+), B220(+) cells. Despite the insulitis, these mice do not develop diabetes. Transgenic rat insulin promoter-IL -6 mice were therefore also made on an inbred NOD background. These mi ce showed no difference in the onset or extent of insulitis when compa red with non-transgenic NOD mice and no difference was found in the ph enotype of the infiltrating cells, However, transgenic NOD mice had lo wer average fasting glucose levels and delayed onset of diabetes compa red with age and sex matched littermate negative NOD mice. As a conseq uence, transgenic NOD mice also had longer survival than littermate ne gative NOD mice. We conclude that the expression of IL-6 by beta cells does not cause insulitis or diabetes in C57BL/6 x CBA mice, but that the interaction of IL-6 and diabetes susceptibility genes causes insul itis in NOD/F-1 mice. Since IL-6 delays the onset of diabetes and prol ongs survival of NOD mice, it is possible that the protective effect i s caused by local IL-6 action on the islets, by the infiltrating lymph ocytes or both.