Leishmania major inhibits IL-12 in macrophages by signalling through CR3 (CD11b/CD18) and down-regulation of ETS-mediated transcription.
Leishmania major inhibits IL-12 in macrophages by signalling through CR3 (CD11b/CD18) and down-regulation of ETS-mediated transcription.
复制标题
重大利什曼原虫通过 CR3 (CD11b/CD18) 信号传导和 ETS 介导的转录下调来抑制巨噬细胞中的 IL-12。
DOI：
10.1111/pim.12049
复制
发表时间：
2013
影响因子：
2.2
通讯作者：
McDowell,MA
中科院分区：
文献类型：
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作者：
Ricardo-Carter,C;Favila,M;Polando,RE;Cotton,RN;BogardHorner,K;Condon,D;Ballhorn,W;Whitcomb,JP;Yadav,M;Geister,RL;Schorey,JS;McDowell,MA
大利什曼原虫是皮肤利什曼病的病原体。这种寄生虫主要感染哺乳动物宿主中的免疫哨兵细胞，特别是巨噬细胞和树突状细胞。感染是由受体介导的，已知涉及寄生虫与细胞表面蛋白补体受体3(CR3，Mac-1，CD11b/CD18)的结合。CR3与各种配体的结合抑制了IL-12(IL-12)的产生，IL-12是驱动抗利什曼T辅助1型免疫反应的细胞因子。同样，主要乳杆菌感染抑制宿主巨噬细胞IL-12的产生和激活。我们的数据表明，在没有CR3的情况下，主要感染的骨髓来源的巨噬细胞在脂多糖(LPS)刺激下比WT细胞产生更多的IL-12和一氧化氮。因此，我们研究了主要通过CR3连接抑制IL-12转录的多条信号通路。我们证明，在WT或CD11b缺陷的巨噬细胞中，L.C.主要感染并不能诱导显著的NFκB p65、MAPK、IRF-1或IRF-8的激活。此外，感染既不能抑制脂多糖诱导的MAPK或NFκB的激活，也不能阻断干扰素-γ激活的IRF-1和IRF-8。然而，Ets介导的转录被抑制。我们的数据表明，IL-12的主要抑制作用是通过CR3结合实现的，但其抑制机制不依赖于核因子κB、丝裂原活化蛋白K、免疫抑制因子和内毒素。
Leishmania majoris an aetiological agent of cutaneous leishmaniasis. The parasite primarily infects immune sentinel cells, specifically macrophages and dendritic cells, in the mammalian host. Infection is receptor mediated and is known to involve parasite binding to cell surface protein complement receptor 3 (CR3, Mac‐1, CD11b/CD18). Engagement of CR3 by various ligands inhibits production of interleukin‐12 (IL‐12), the cytokine that drives antileishmanial T helper 1‐type immune responses. Likewise,L. majorinfection inhibits IL‐12 production and activation of host macrophages. Our data indicate that in the absence of CR3,L. major‐infected bone marrow‐derived macrophages produce more IL‐12 and nitric oxide compared with WT cells upon lipopolysaccharide (LPS) stimulation. We therefore investigated multiple signalling pathways by whichL. majormay inhibit IL‐12 transcription through CR3 ligation. We demonstrate thatL. majorinfection does not elicit significant NFκB p65, MAPK, IRF‐1 or IRF‐8 activation in WT or CD11b‐deficient macrophages. Furthermore, infection neither inhibits LPS‐induced MAPK or NFκB activation nor blocks IFN‐γ‐activated IRF‐1 and IRF‐8. ETS‐mediated transcription, however, is inhibited byL. majorinfection independently of CR3. Our data indicate thatL. major‐mediated inhibition of IL‐12 occurs through CR3 engagement; however, the mechanism of inhibition is independent of NFκB, MAPK, IRF and ETS.