Trypanosoma cruzi-mediated IFN-γ-inducible nitric oxide output in macrophages is regulated by iNOS mRNA stability
Trypanosoma cruzi-mediated IFN-γ-inducible nitric oxide output in macrophages is regulated by iNOS mRNA stability
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DOI：
10.4049/jimmunol.177.9.6271
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发表时间：
2006-11-01
影响因子：
4.4
通讯作者：
Olivier, Martin
中科院分区：
文献类型：
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作者：
Bergeron, Marc;Olivier, Martin
虽然活化的巨噬细胞（M phi）对细胞内寄生虫克氏锥虫的影响是有据可查的，但很少有人知道宿主M phi功能在活化前如何受到这种病原体的影响。本研究旨在评估T. cruzi感染以调节IFN-γ刺激后J77.4鼠M phi NO产生，并鉴定调节这种调节的机制。结果表明，寄生虫感染增强M phi产生诱导型NO合酶（iNOS）mRNA和蛋白以及在IFN-γ刺激后高于单独的IFN-γ对照的NO。这种增强作用是通过NF-κ B B、ERK 1/ERK 2 MAPK和应激活化蛋白激酶信号通路的同时激活而发生的。通过IFN-γ激活JAK/STAT途径，然后导致STAT 1 α易位和稳定的iNOS mRNA种类的转录。iNOS mRNA降解速率降低导致iNOS蛋白水平升高和NO产生。最大的iNOS表达可能是通过T激活NF-κ B而实现的。cruzi，而iNOSmRNA稳定性的结果从ERK 1/ERK 2 MAPK和应激活化蛋白激酶激活的感染。综合起来，我们的数据表明，T. cruzi感染的M phi NO的产生在转录前和转录后水平上都受到控制，并且依赖于信号传导途径的串扰。这是首次报道能够提高宿主mRNA稳定性的寄生虫病原体。
Although the effects of activated macrophages (M phi) on the intracellular parasite Trypanosoma cruzi are well documented, little is known about how host-M phi functions are affected by this pathogen before activation. This study is aimed at assessing the capacity of T. cruzi infection to modulate J77.4 murine M phi NO generation following IFN-gamma stimulation, and identifying mechanisms regulating this modulation. Results show that parasite infection potentiates M phi to produce inducible NO synthase (iNOS) mRNA and protein as well as NO following IFN-gamma stimulation above IFN-gamma alone controls. This potentiation occurs through the concomitant activation of NF-kappa B, ERK1/ERK2 MAPK, and stress-activated protein kinase signaling pathways. Activation of the JAK/STAT pathway by IFN-gamma then leads to STAT1 alpha translocation and the transcription of a stable iNOS mRNA species. A decreased rate of iNOS mRNA degradation results in elevated levels of iNOS protein, and NO production. Maximal iNOS expression is likely achieved through NF-kappa B activation by T. cruzi, whereas iNOS mRNA stability results from ERK1/ERK2 MAPK and stress-activated protein kinase activation by the infection. Taken together, our data show that T. cruzi-infected M phi NO generation is controlled at both pre- and posttranscriptional levels and relies on signaling pathway cross-talk. This is the first report of a parasite pathogen capable of heightening host mRNA stability.