Toxoplasma gondii interferes with lipopolysaccharide-induced mitogen-activated protein kinase activation by mechanisms distinct from endotoxin tolerance
Toxoplasma gondii interferes with lipopolysaccharide-induced mitogen-activated protein kinase activation by mechanisms distinct from endotoxin tolerance
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DOI：
10.4049/jimmunol.172.5.3003
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发表时间：
2004-03-01
影响因子：
4.4
通讯作者：
Denkers, EY
中科院分区：
文献类型：
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作者：
Kim, L;Butcher, BA;Denkers, EY
我们在这项研究中发现，弓形虫感染诱导小鼠巨噬细胞中p38丝裂原激活蛋白激酶（MAPK）、细胞外信号调节激酶1/2和应激激活蛋白激酶/c-Jun n末端激酶MAPK的快速激活，随后迅速失活。然而，当感染细胞随后受到LPS触发时，MAPK的激活严重缺陷，特别是在p38 MAPK的情况下，p38 MAPK是LPS触发的tnf - α和IL-12产生所必需的。内毒素耐受性也有类似的效果，但现象不同。LPS预触发未能激活主要的p38 MAPK激酶，MAPK激酶3/6。相比之下，弓形虫感染导致这种激酶的持续激活。此外，内毒素预暴露阻断了随后LPS触发的IkappaBalpha降解，但弓形虫预感染并非如此。内毒素介导的LPS受体toll样受体4的下调被认为是促成耐受性的一种可能机制，我们在本研究中发现LPS下调toll样受体4的表达。相反，弓形虫感染诱导了这种模式识别受体的上调。我们的研究结果表明，弓形虫阻断lps触发的细胞因子产生部分是通过MAPK失活，而这是通过不同于内毒素诱导耐受的途径发生的。
We show in this study that Toxoplasma gondii infection induces rapid activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2, and stress-activated protein kinase/c-Jun N-terminal kinase MAPK, followed promptly by their deactivation in mouse macrophages. Nevertheless, when infected cells were subsequently subjected to LPS triggering, MAPK activation was severely defective, in particular in the case of p38 MAPK, which is required for LPS-triggered TNF-alpha and IL-12 production. Similar effects occurred during endotoxin tolerance, but the phenomena were distinct. LPS pretriggering failed to activate the major p38 MAPK kinase, MAPK kinase 3/6. Toxoplasma infection, in contrast, resulted in sustained activation of this kinase. Furthermore, endotoxin pre-exposure blocked IkappaBalpha degradation upon subsequent LPS triggering, but this was not the case for Toxoplasma preinfection. Endotoxin-mediated down-regulation of the LPS receptor, Toll-like receptor 4, has been suggested as one possible mechanism contributing to tolerance, and we found in this study that LPS down-modulated Toll-like receptor 4 expression. In contrast, Toxoplasma infection induced up-regulation of this pattern recognition receptor. Our results show that T. gondii blocks LPS-triggered cytokine production in part through MAPK inactivation, and that this occurs through pathways distinct from endotoxin-induced tolerance.