IL-18 inhibits diabetes development in nonobese diabetic mice by counterregulation of Th1-dependent destructive insulitis

The development of type 1 diabetes in animal models is T cell and macrophag e dependent. Islet inflammation begins as peripheral benign Th2 type insuli tis and progresses to destructive Th1 type insulitis, which is driven by th e innate immune system via secretion of IL-12 and IL-18, We now report that daily application of IL-18 to diabetes-prone female nonobese diabetic mice , starting at 10 wk of age, suppresses diabetes development (p < 0.001, 65% in sham-treated animals vs 33% in IL-18-treated animals by 140 days of age ). In IL-18-treated animals, we detected significantly lower intraislet inf iltration (p < 0.05) and concomitantly an impaired progression from Th2 ins ulitis to Th1-dependent insulitis, as evidenced from IFN-gamma and IL-10 mR NA levels in tissue. The deficient progression was probably due to lesser m RNA expression of the Th1 driving cytokines IL-12 and IL-18 by the innate i mmune system (p < 0.05), Furthermore, the mRNA expression of inducible NO s ynthase, a marker of destructive insulitis, was also not up-regulated in th e IL-18-treated group. IL-18 did not exert its effect at the levels of isle t cells. Cultivation of islets with IL-18 affected NO production or mitocho ndrial activity and did not protect from the toxicity mediated by IL-1 beta , TNF-alpha, and IFN-gamma, In conclusion, we show for the first time that administration of IL-18, a mediator of the innate immune system, suppresses autoimmune diabetes in nonobese diabetic mice by targeting the Th1/Th2 bal ance of inflammatory immune reactivity in the pancreas.