Nascimento Flávia R F, Calich Vera L G, Rodríguez Dunia, Russo Momtchilo
Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de Sao Paulo, Sao Paulo, Brazil.
J Immunol. 2002 May 1;168(9):4593-600. doi: 10.4049/jimmunol.168.9.4593.
Using a murine model of susceptibility and resistance to paracoccidioidomycosis, we have previously demonstrated that immunosuppression occurs in susceptible (B10.A), but not in resistant (A/Sn), mouse strains. Accumulating evidence shows that NO is involved in the induction of T cell immunosuppression during infection as well as in the killing of Paracoccidioides brasiliensis. In the present work, we focused on NO and other macrophage products that could be associated with resistance or susceptibility to paracoccidioidomycosis. A striking difference was related to NO and TNF production. Macrophages from B10.A mice produced high and persistent NO levels, while in A/Sn animals, TNF production predominated. In in vitro cultures, P. brasiliensis-infected macrophages from A/Sn mice also produced large amounts of TNF, while B10.A macrophages only produced NO. TNF production by B10.A macrophages appeared to be suppressed by NO, because the addition of aminoguanidine sulfate, an inducible NO synthase (NOS2) inhibitor, resulted in TNF production. These results suggested that enhanced TNF or NO production is associated with resistance and susceptibility, respectively. However, regardless of the mouse strain, NOS2-deficient or aminoguanidine sulfate-treated mice presented extensive tissue lesions with increased fungal load in lungs and liver compared with their controls. We conclude that NOS2-derived NO is essential for resistance to paracoccidioidomycosis, but overproduction is associated with susceptibility.
利用对副球孢子菌病易感和有抵抗力的小鼠模型，我们先前已证明免疫抑制发生在易感（B10.A）小鼠品系中，而在有抵抗力的（A/Sn）小鼠品系中则未发生。越来越多的证据表明，一氧化氮（NO）在感染期间T细胞免疫抑制的诱导以及巴西副球孢子菌的杀伤中都起作用。在本研究中，我们聚焦于NO和其他可能与副球孢子菌病的抵抗力或易感性相关的巨噬细胞产物。一个显著差异与NO和肿瘤坏死因子（TNF）的产生有关。来自B10.A小鼠的巨噬细胞产生高水平且持续的NO，而在A/Sn小鼠中，TNF的产生占主导。在体外培养中，来自A/Sn小鼠的受巴西副球孢子菌感染的巨噬细胞也产生大量TNF，而B10.A巨噬细胞仅产生NO。B10.A巨噬细胞产生TNF的能力似乎被NO抑制，因为添加硫酸氨基胍（一种诱导型一氧化氮合酶（NOS2）抑制剂）会导致TNF产生。这些结果表明，TNF产生增强或NO产生增强分别与抵抗力和易感性相关。然而，无论小鼠品系如何，与对照相比，NOS2缺陷或经硫酸氨基胍处理的小鼠肺部和肝脏出现广泛的组织病变且真菌负荷增加。我们得出结论，NOS2衍生的NO对副球孢子菌病的抵抗力至关重要，但过量产生与易感性相关。
