Luckhart Shirley, Lieber Matthew J, Singh Naresh, Zamora Ruben, Vodovotz Yoram
University of California at Davis, Department of Medical Microbiology and Immunology, 3437 Tupper Hall, One Shields Avenue, School of Medicine, Davis, CA 95616, USA.
Exp Parasitol. 2008 Feb;118(2):290-6. doi: 10.1016/j.exppara.2007.08.013. Epub 2007 Sep 2.
Nitric oxide (NO), derived from catalysis of inducible NO synthase (iNOS), limits malaria parasite growth in mammals. Transforming growth factor (TGF)-beta1 suppresses iNOS in cells in vitro as well as in vivo in mice, but paradoxically severe malaria in humans is associated with low levels of TGF-beta1. We hypothesized that this paradox is a universal feature of infection and occurs in the mosquito Anopheles stephensi, an invertebrate host for Plasmodium that also regulates parasite development with inducible NO synthase (AsNOS). We show that exogenous human TGF-beta1 dose-dependently regulates mosquito AsNOS expression and that parasite killing by low dose TGF-beta1 depends on AsNOS catalysis. Furthermore, induction of AsNOS expression by TGF-beta1 is regulated by NO synthesis. These results suggest that TGF-beta1 plays similar roles during parasite infection in mammals and mosquitoes and that this role is linked to the effects of TGF-beta1 on inducible NO synthesis.
一氧化氮（NO）由诱导型一氧化氮合酶（iNOS）催化产生，可限制疟原虫在哺乳动物体内的生长。转化生长因子（TGF）-β1在体外细胞以及小鼠体内均能抑制iNOS，但矛盾的是，人类严重疟疾与低水平的TGF-β1相关。我们推测，这种矛盾现象是感染的普遍特征，在冈比亚按蚊中也会出现，冈比亚按蚊是疟原虫的无脊椎宿主，它也通过诱导型一氧化氮合酶（AsNOS）调节寄生虫的发育。我们发现，外源性人类TGF-β1剂量依赖性地调节蚊子AsNOS的表达，低剂量TGF-β1对寄生虫的杀伤作用依赖于AsNOS催化。此外，TGF-β1对AsNOS表达的诱导作用受NO合成的调节。这些结果表明，TGF-β1在哺乳动物和蚊子的寄生虫感染过程中发挥相似作用，且该作用与TGF-β1对诱导型NO合成的影响有关。
