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
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
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DOI：
10.1046/j.1365-3024.1999.00237.x
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发表时间：
1999-07-01
影响因子：
2.2
通讯作者：
Suzuki, Y
中科院分区：
文献类型：
--
作者：
Liesenfeld, O;Kang, H;Suzuki, Y
我们以前报道过小鼠经口感染T。弓形虫感染与CD 4（+）T细胞依赖性、干扰素（IFN）-γ介导的小肠坏死有关。我们研究了肿瘤坏死因子（TNF）-α和一氧化氮（NO）的作用，除了IFN-γ。在感染后7天，与正常小鼠相比，在小肠固有层单核细胞（LPC）中观察到CD 4（+）T细胞显著增加，并且在感染动物的小肠LPC中检测到IFN-γ、TNF-α和诱导型NO合酶（iNOS）的mRNA量显著高于未感染动物。用抗TNF-α单克隆抗体（mAb）或iNOS抑制剂氨基胍治疗感染的小鼠，可预防坏死并延长死亡时间。感染的iNOS靶向突变小鼠没有发生疾病，而感染的对照小鼠发生了疾病。用抗TNF-α mAb治疗不影响LPC中IFN-γ的表达，但抑制感染小鼠中iNOS的表达，表明TNF-α在诱导iNOS中的作用。这些结果表明，通过激活iNOS的IFN-γ和TNF-α的组合诱导的NO是肠道病理学的关键介质，并导致遗传易感小鼠的早期死亡率。
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.