Novel role for the double-stranded RNA-activated protein kinase PKR: modulation of macrophage infection by the protozoan parasite Leishmania
Novel role for the double-stranded RNA-activated protein kinase PKR: modulation of macrophage infection by the protozoan parasite Leishmania
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DOI：
10.1096/fj.09-140053
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发表时间：
2010-02-01
期刊：
影响因子：
4.8
通讯作者：
Lopes, Ulisses G.
中科院分区：
文献类型：
--
作者：
Pereira, Renata M. S.;Dias Teixeira, Karina Luiza;Lopes, Ulisses G.
利什曼原虫感染的进化取决于巨噬细胞杀微生物和抑制功能之间的平衡。双链RNA （dsRNA）激活蛋白激酶R （PKR）是一种经典的抗病毒蛋白，能够调节多种信号通路和巨噬细胞功能。我们研究了PKR在利什曼原虫感染调节中的可能作用。我们的数据表明，亚马逊利什曼原虫感染导致PKR激活和PKR水平升高。同样，在敲除PKR的129Sv/Ev小鼠的巨噬细胞和稳定表达PKR显性阴性（DN）结构（DN-PKR）的RAW-264.7细胞中，亚马逊乳杆菌感染明显减少。用合成的双链RNA poly(I: C)（一种有效的PKR诱导剂）处理感染的巨噬细胞，增加了亚马逊乳杆菌的细胞内增殖。2-氨基嘌呤（2-AP），一种PKR的药理学抑制剂，以及DN-PKR的表达可以逆转这种作用。通过NF-kappa B调节，amazonensis可以抑制dsRNA诱导的NO释放。dsRNA诱导的PKR激活也导致IL-10的产生，IL-10被特异性抗体中和后完全消除了亚马逊乳杆菌的增殖。我们的数据表明PKR通过IL-10调节在原虫寄生虫感染中的新作用。-Pereira， R. M. S, Teixeira， K. L. D, Barreto-deSouza， V. Calegari-Silva， T. C, De-Melo， D. B, Soares， D. C, bouh - habib， D. C, Silva， A. M, Saraiva， E. M, Lopes， U. G.双链rna激活蛋白激酶PKR的新作用：调节原虫原虫利什曼原虫的巨噬细胞感染。中国生物医学工程学报，2009,32(2):444 - 444。www.fasebj.org
The evolution of Leishmania infection depends on the balance between microbicidal and suppressor macrophage functions. Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a classic antiviral protein, is able to regulate a number of signaling pathways and macrophage functions. We investigated the possible role of PKR in the modulation of Leishmania infection. Our data demonstrated that Leishmania amazonensis infection led to PKR activation and increased PKR levels. Consistently, in macrophages from PKR knockout 129Sv/Ev mice and RAW-264.7 cells stably expressing a dominant-negative (DN) construct of PKR (DN-PKR), L. amazonensis infection was strongly reduced. The treatment of infected macrophages with the synthetic double-stranded RNA poly(I: C), a potent PKR inductor, increased L. amazonensis intracellular proliferation. This effect was reversed by 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, as well as by the expression of DN-PKR. NO release induced by dsRNA treatment was inhibited by L. amazonensis through NF-kappa B modulation. PKR activation induced by dsRNA also resulted in IL-10 production, whose neutralization with specific antibody completely abrogated L. amazonensis proliferation. Our data demonstrated a new role of PKR in protozoan parasitic infection through IL-10 modulation.-Pereira, R. M. S., Teixeira, K. L. D., Barreto-deSouza, V. Calegari-Silva, T. C., De-Melo, D. B., Soares, D. C., Bou-Habib, D. C., Silva, A. M., Saraiva, E. M., Lopes, U. G. Novel role for the double-stranded RNA-activated protein kinase PKR: modulation of macrophage infection by the protozoan parasite Leishmania. FASEB J. 24, 617-626 (2010). www.fasebj.org