p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection
p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection
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DOI：
10.4049/jimmunol.174.7.4178
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发表时间：
2005-04-01
影响因子：
4.4
通讯作者：
Denkers, EY
中科院分区：
文献类型：
--
作者：
Kim, L;Del Rio, L;Denkers, EY
细胞内原生动物弓形虫可在小鼠巨噬细胞(M Phi)中快速激活MAPK。我们使用合成的抑制剂和显性阴性的Mphi突变体来证明弓形虫依赖于p38MAPK来触发IL-12的产生。应激激活蛋白激酶/JNK的化学抑制表明，该MAPK也是寄生虫触发的IL-12产生所必需的。对作为P38 MAPK激活蛋白的上游MAPK激酶(MKK)3、4和6的检测表明，寄生虫感染只激活MKK3，而在MKK3(-/-)MPhi中，p38MAPK活性接近正常，而IL-12的产生没有受到影响。最近，通过自身磷酸化来激活不依赖MKK的p38αMAPK已被报道。自磷酸化依赖于P38A MAPK与接头蛋白--转化生长因子-β活化蛋白激酶1结合蛋白-1的结合。我们观察到在弓形虫感染的过程中，转化生长因子-β活化的蛋白激酶1结合蛋白-1-p38αMAPK与p38MAPK的磷酸化密切相关。此外，合成的p38催化位抑制物可阻断速殖子诱导的p38αMAPK的磷酸化。这些数据首次证明了p38 MAPK的自磷酸化是由细胞内感染触发的。
The intracellular protozoan Toxoplasma gondii triggers rapid MAPK activation in mouse macrophages (M phi). We used synthetic inhibitors and dominant-negative M phi mutants to demonstrate that T. gondii triggers IL-12 production in dependence upon p38 MAPK. Chemical inhibition of stress-activated protein kinase/JNK showed that this MAPK was also required for parasite-triggered IL-12 production. Examination of upstream MAPK kinases (MKK) 3, 4, and 6 that function as P38 MAPK activating kinases revealed that parasite infection activates only MKK3 Nevertheless, in MKK3(-/-) M phi, p38 MAPK activation was near normal and IL-12 production was unaffected. Recently, MKK-independent p38 alpha MAPK activation via autophosphorylation was described. Autophosphorylation depends upon p38a MAPK association with adaptor protein, TGF-beta-activated protein kinase 1-binding protein-1. We observed TGF-beta-activated protein kinase 1-binding protein-1-p38 alpha MAPK association that closely paralleled p38 MAPK phosphorylation during Toxoplasma infection of M phi. Furthermore, a synthetic p38 catalytic-site inhibitor blocked tachyzoite-induced p38 alpha MAPK phosphorylation. These data are the first to demonstrate p38 MAPK autophosphorylation triggered by intracellular infection.