Strategies of protection from nitric oxide toxicity in islet inflammation

Nitric oxide is thought to contribute to beta cell destruction during islet inflammation in animal models of type I diabetes. In vitro, inhibition of inducible nitric oxide synthase protects islet cells from the damaging effe cts of inflammatory cells or cytokines. However, the administration of seve ral inducible nitric oxide synthase inhibitors to prediabetic animals had v ariable effects on disease-progression. An alternative approach is to preve nt the lethal consequences of nitric oxide action at the level of islet cel ls. We observed that the suppression of poly-(ADP-ribose)-polymerase ensure s survival of islet cells exposed to nitric oxide. Cells could also be rend ered resistant by the induction of endogenous stress proteins in particular of heat shock protein 70. Nitric oxide is not only a strong cytotoxic agen t, but is also able to modulate immune reactions by interfering with Th1/Th 2 reactivities. This may occur via induction of the interleukin-l, antagoni st IL-12(p40)(2). Development of type I diabetes is known to be correlated with a shift from a Th2 status during benign insulitis to a Th1 status duri ng destructive insulitis. This shift was found dependent on local interleuk in-la gene expression. Indeed, administration of a natural interleukin-12 a ntagonist suppressed the progression of islet inflammation and concomitant upregulation of the inducible nitric oxide synthase.