Strategies of protection from nitric oxide toxicity in islet inflammation

J Mol Med (Berl). 1999 Jan;77(1):40-4. doi: 10.1007/s001090050298.

Abstract

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 effects of inflammatory cells or cytokines. However, the administration of several inducible nitric oxide synthase inhibitors to prediabetic animals had variable effects on disease progression. An alternative approach is to prevent the lethal consequences of nitric oxide action at the level of islet cells. We observed that the suppression of poly-(ADP-ribose)-polymerase ensures survival of islet cells exposed to nitric oxide. Cells could also be rendered resistant by the induction of endogenous stress proteins in particular of heat shock protein 70. Nitric oxide is not only a strong cytotoxic agent, but is also able to modulate immune reactions by interfering with Th1/Th2 reactivities. This may occur via induction of the interleukin-12 antagonist IL-12(p40)2. Development of type 1 diabetes is known to be correlated with a shift from a Th2 status during benign insulitis to a Th1 status during destructive insulitis. This shift was found dependent on local interleukin-12 gene expression. Indeed, administration of a natural interleukin-12 antagonist suppressed the progression of islet inflammation and concomitant upregulation of the inducible nitric oxide synthase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / physiopathology*
  • Interleukin-12 / antagonists & inhibitors
  • Interleukin-12 / physiology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Mice
  • Mice, Inbred NOD
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase Type II
  • Poly(ADP-ribose) Polymerases / metabolism
  • T-Lymphocytes / immunology

Substances

  • Interleukin-12
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Poly(ADP-ribose) Polymerases