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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
Author(s) -
LIESENFELD OLIVER,
KANG HOIL,
PARK DANIEL,
NGUYEN THU A.,
PARKHE CHANDAN V.,
WATANABE HISAMI,
ABO TORU,
SHER ALAN,
REMINGTON JACK S.,
SUZUKI YASUHIRO
Publication year - 1999
Publication title -
parasite immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.795
H-Index - 75
eISSN - 1365-3024
pISSN - 0141-9838
DOI - 10.1046/j.1365-3024.1999.00237.x
Subject(s) - toxoplasma gondii , biology , nitric oxide , immunology , tumor necrosis factor alpha , necrosis , virology , microbiology and biotechnology , endocrinology , antibody , genetics
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 .