Leishmania donovani suppresses activated protein 1 and NF-κB activation in host macrophages via ceramide generation:: Involvement of extracellular signal-regulated kinase
Leishmania donovani suppresses activated protein 1 and NF-κB activation in host macrophages via ceramide generation:: Involvement of extracellular signal-regulated kinase
复制标题
DOI：
10.1128/iai.70.12.6828-6838.2002
复制
发表时间：
2002-12-01
影响因子：
3.1
通讯作者：
Majumdar, S
中科院分区：
文献类型：
--
作者：
Ghosh, S;Bhattacharyya, S;Majumdar, S
在体外感染小鼠腹腔巨噬细胞与原虫杜氏利什曼原虫已被发现改变宿主的信号参数。本研究表明，感染后巨噬细胞内神经酰胺水平的增加是与巨噬细胞功能障碍有关的主要事件。我们以前已经证明，增加宿主巨噬细胞中的神经酰胺合成参与细胞外信号调节激酶（ERK）的去磷酸化。在本研究中，我们进一步表明，下调ERK的神经酰胺被发现与抑制活化蛋白1（AP-1）和NF-κ B反式激活。伏马菌素B1对神经酰胺合成的药理学抑制恢复了感染的BALB/c巨噬细胞中AP-1和NF-κ B DNA结合活性的诱导。相反，在来自抗利什曼病的C.D2小鼠的巨噬细胞的情况下，L. donovani不能诱导持续的神经酰胺合成。在L.感染的C.D2巨噬细胞。ERK的激活对于转录因子AP-1和NF-κ B的激活、NO的产生以及在抗性鼠宿主巨噬细胞中寄生虫负荷的限制是必需的。因此，宿主巨噬细胞中神经酰胺合成的诱导似乎是有用的，并且是导致巨噬细胞抗利什曼反应沉默的转折点之一。
In vitro infection of murine peritoneal macrophages with the protozoan Leishmania donovani has been found to alter the signaling parameters of the host. The present study indicates that the enhancement of intracellular ceramide level in macrophages after infection is a major event relating to macrophage dysfunction. We have previously demonstrated that increased ceramide synthesis in host macrophages was involved in the dephosphorylation of extracellular signal-regulated kinase (ERK). In the present study, we further show that downregulation of ERK by ceramide was found to be associated with the inhibition of activated protein 1 (AP-1) and NF-kappaB transactivation. Pharmacological inhibition of ceramide synthesis by Fumonisin B1 restored the induction of AP-1 and NF-kappaB DNA-binding activities in infected BALB/c macrophages. On the contrary, in the case of macrophages from the leishmaniasis-resistant C.D2 mice, L. donovani failed to induce sustained ceramide synthesis. Enhanced mitogen-activated protein kinase phosphorylation, AP-1 and NF-kappaB DNA-binding activity, and the generation of nitric oxide (NO) were observed in L. donovani-infected C.D2 macrophages. ERK activation was necessary for the activation of transcription factors AP-1 and NF-kappaB, NO generation, and restriction of the parasite burden in the resistant murine host macrophages. Hence, the induction of ceramide synthesis in host macrophages appears to be instrumental and one of the turning points leading to silencing of the macrophage antileishmanial responses.