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

Oliver Liesenfeld, Hoil Kang, Daniel Park, Thu A. Nguyen, Chandan V. Parkhe, Hisami Watanabe, Toru Abo, Alan Sher, Jack S. Remington, Yasuhiro Suzuki

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

We previously reported that genetic susceptibility of mice to peroral infection with T. gondii is associated with CD4+ T cell-dependent, interferon (IFN)-γ-mediated necrosis of their small intestine. We examined the role of tumour necrosis factor (TNF)-α and nitric oxide (NO), in addition to IFN-γ. 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-γ, TNF-α, 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-α 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-α mAb did not affect the expression of IFN-γ in the LPC but inhibited expression of iNOS in the infected mice, indicating the role of TNF-α in the induction of iNOS. These results suggest that NO induced by a combination of IFN-γ and TNF-α through activation of iNOS is a critical mediator of intestinal pathology and contributes to early mortality in genetically susceptible mice.

Original languageEnglish
Pages (from-to)365-376
Number of pages12
JournalParasite Immunology
Volume21
Issue number7
DOIs
StatePublished - 1999

Keywords

  • Genetic susceptibility
  • Interferon-γ
  • Intestine
  • Necrosis
  • Nitric oxide
  • Toxoplasma gondii
  • Tumour necrosis factor-α

ASJC Scopus subject areas

  • Parasitology
  • Immunology

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