TNF-alpha, nitric oxide and IFN-gamma are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii

Parasite Immunol. 1999 Jul;21(7):365-76. doi: 10.1046/j.1365-3024.1999.00237.x.

Abstract

We previously reported that genetic susceptibility of mice to peroral infection with T. gondii is associated with CD4+ T cell-dependent, interferon (IFN)-gamma-mediated necrosis of their small intestine. We examined the role of tumour necrosis factor (TNF)-alpha and nitric oxide (NO), in addition to IFN-gamma. At 7 days after infection, a marked increase in CD4+ T cells was observed in lamina propria mononuclear cells (LPC) of the small intestine as compared with normal mice, and significantly greater amounts of mRNA for IFN-gamma, TNF-alpha, and inducible NO synthase (iNOS) were detected in LPC of the small intestine of infected than uninfected animals. Treatment of infected mice with anti-TNF-alpha monoclonal antibody (mAb) or the iNOS inhibitor, aminoguanidine, prevented necrosis and prolonged time to death. Infected iNOS-targeted mutant mice did not develop the disease whereas infected, control mice did. Treatment with anti-TNF-alpha mAb did not affect the expression of IFN-gamma in the LPC but inhibited expression of iNOS in the infected mice, indicating the role of TNF-alpha in the induction of iNOS. These results suggest that NO induced by a combination of IFN-gamma and TNF-alpha through activation of iNOS is a critical mediator of intestinal pathology and contributes to early mortality in genetically susceptible mice.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Flow Cytometry
  • Genetic Predisposition to Disease
  • Ileum / immunology
  • Ileum / pathology*
  • Interferon-gamma / genetics
  • Interferon-gamma / physiology*
  • Intestinal Diseases, Parasitic / immunology
  • Intestinal Diseases, Parasitic / parasitology
  • Intestinal Diseases, Parasitic / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Necrosis
  • Nitric Oxide / physiology*
  • Polymerase Chain Reaction
  • Toxoplasma / physiology
  • Toxoplasmosis, Animal / immunology*
  • Toxoplasmosis, Animal / parasitology
  • Toxoplasmosis, Animal / pathology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Interferon-gamma