CD40 signaling is impaired in L. major-infected macrophages and is rescued by a p38MAPK activator establishing a host-protective memory T cell response
CD40 signaling is impaired in L. major-infected macrophages and is rescued by a p38MAPK activator establishing a host-protective memory T cell response
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DOI：
10.1084/jem.20022033
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发表时间：
2003-04-21
影响因子：
15.3
通讯作者：
Saha, B
中科院分区：
文献类型：
--
作者：
Awasthi, A;Mathur, R;Saha, B
利什曼原虫是一种原生动物寄生虫，在巨噬细胞内作为无鞭毛体生活和繁殖。研究表明，巨噬细胞表达的CD 40与T细胞上的CD 40配体相互作用，诱导IFN-γ，一种限制无鞭毛体生长的Th 1型细胞因子。在这里，我们表明，CD 40交联感染后早期导致诱导型一氧化氮合成酶2型（iNOS 2）的诱导和iNOS 2依赖性无鞭毛体消除。虽然在L.主要感染的巨噬细胞，延迟用抗CD 40抗体治疗巨噬细胞或小鼠导致iNOS 2表达和杀利什曼功能的显著降低，表明利什曼原虫感染中受损的CD 40信号传导。p38丝裂原活化蛋白激酶（p38 MAPK）特异性抑制剂SB 203580可抑制CD 40诱导的iNOS 2表达，p38 MAPK激活剂茴香霉素可逆转其抑制作用，提示p38 MAPK在CD 40信号转导中起重要作用。事实上，CD 40诱导的p38 MAPK磷酸化，iNOS 2表达和抗利什曼原虫功能在利什曼原虫感染的巨噬细胞中受损，但被茴香霉素恢复。茴香霉素的作用被SB 203580逆转，强调了p38 MAPK在CD 40诱导的iNOS 2依赖的杀利什曼功能中的作用。茴香霉素对L.主要感染的BALB/c小鼠导致寄生虫负荷的显着减少，并建立了宿主保护性Th 1型记忆反应。这些发现还涉及确定新的抗寄生虫药物靶点和绕过耐药性问题的科学原理。
Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-gamma, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major-infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK) -specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD40-induced p38MAPK phosphorylation, iNOS2 expression and anti-leishmanial function were impaired in Leishmania-infected macrophages but were restored by anisomycin. Anisomycin's effects were reversed by SB203580 emphasizing the role of p38MAPK in CD40-induced iNOS2-dependent leishmanicidal function. Anisomycin administration in L. major-infected BALB/c mice resulted in significant reduction in the parasite load and established a host-protective Th1-type memory response. Also implicated in these findings is a scientific rationale to define novel anti-parasite drug targets and to bypass the problem of drug resistance.