Intracellular Networks of the PI3K/AKT and MAPK Pathways for Regulating Toxoplasma gondii-Induced IL-23 and IL-12 Production in Human THP-1 Cells.
Intracellular Networks of the PI3K/AKT and MAPK Pathways for Regulating Toxoplasma gondii-Induced IL-23 and IL-12 Production in Human THP-1 Cells.
复制标题
调节人 THP-1 细胞中弓形虫诱导的 IL-23 和 IL-12 产生的 PI3K/AKT 和 MAPK 通路的细胞内网络
DOI：
10.1371/journal.pone.0141550
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lee YH
中科院分区：
文献类型：
--
作者：
Quan JH;Chu JQ;Kwon J;Choi IW;Ismail HA;Zhou W;Cha GH;Zhou Y;Yuk JM;Jo EK;Lee YH
白细胞介素（IL）-23和IL-12在结构上密切相关，并且这些细胞因子调节天然免疫和获得性免疫。然而，在刚地弓形虫感染的THP-1单核细胞中调节每种蛋白产生的精确信号网络，特别是PI 3 K/AKT和MAPK信号通路，仍然未知。在本研究中，T.弓形虫感染可上调THP-1细胞中IL-23和IL-12的表达，且这两种细胞因子的表达均随弓形虫感染剂量的增加而增加。IL-23分泌被TLR 2单克隆抗体（mAb）处理以剂量依赖性方式和TLR 2 siRNA转染强烈抑制，而IL-12分泌被TLR 4 mAb处理以剂量依赖性方式和TLR 4 siRNA转染强烈抑制。IL-23的产生被PI 3 K抑制剂LY 294002和渥曼青霉素剂量依赖性地抑制，而IL-12的产生剂量依赖性地增加。THP-1细胞暴露于活T.弓形虫速殖子迅速激活p38 MAPK、ERK 1/2和JNK。p38 MAPK抑制剂SB 203580剂量依赖性地显著上调IL-23的产生，而10 μM SB 203580预处理显著下调IL-12的产生。通过PD 98059抑制ERK 12显著下调IL-23的产生，但上调IL-12的产生。SP 600125抑制JNK可上调IL-23的产生，但IL-12的产生呈剂量依赖性显著下调。T.弓形虫感染导致AKT激活，PI 3 K抑制剂预处理后AKT磷酸化呈剂量依赖性抑制。于T.在感染弓形虫的THP-1细胞中，ERK 1/2的激活受PI 3 K的调节，而p38 MAPK和JNK的磷酸化受PI 3 K信号通路的负调节。总的来说，这些结果表明T.感染弓形虫的THP-1细胞主要受TLR 2的调节，其次是PI 3 K和ERK 12，而IL-12的产生主要受TLR 4的调节，其次是p38 MAPK和JNK。我们的研究结果提供了关于PI 3 K/AKT和MAPK信号级联调节T细胞的细胞内网络的新见解。在人单核细胞中gondii诱导的IL-23和IL-12分泌。
Interleukin (IL)-23 and IL-12 are closely related in structure, and these cytokines regulate both innate and adaptive immunity. However, the precise signaling networks that regulate the production of each in Toxoplasma gondii-infected THP-1 monocytic cells, particularly the PI3K/AKT and MAPK signaling pathways, remain unknown. In the present study, T. gondii infection upregulated the expression of IL-23 and IL-12 in THP-1 cells, and both cytokines increased with parasite dose. IL-23 secretion was strongly inhibited by TLR2 monoclonal antibody (mAb) treatment in a dose-dependent manner and by TLR2 siRNA transfection, whereas IL-12 secretion was strongly inhibited by TLR4 mAb treatment dose-dependently and by TLR4 siRNA transfection. IL-23 production was dose-dependently inhibited by the PI3K inhibitors LY294002 and wortmannin, whereas IL-12 production increased dose-dependently. THP-1 cells exposed to live T. gondii tachyzoites underwent rapid p38 MAPK, ERK1/2 and JNK activation. IL-23 production was significantly upregulated by the p38 MAPK inhibitor SB203580 dose-dependently, whereas pretreatment with 10 μM SB203580 significantly downregulated IL-12 production. ERK1/2 inhibition by PD98059 was significantly downregulated IL-23 production but upregulated IL-12 production. JNK inhibition by SP600125 upregulated IL-23 production, but IL-12 production was significantly downregulated dose-dependently. T. gondii infection resulted in AKT activation, and AKT phosphorylation was inhibited dose-dependently after pretreatment with PI3K inhibitors. In T. gondii-infected THP-1 cells, ERK1/2 activation was regulated by PI3K; however, the phosphorylation of p38 MAPK and JNK was negatively modulated by the PI3K signaling pathway. Collectively, these results indicate that IL-23 production in T. gondii-infected THP-1 cells was regulated mainly by TLR2 and then by PI3K and ERK1/2; however, IL-12 production was mainly regulated by TLR4 and then by p38 MAPK and JNK. Our findings provide new insight concerning the intracellular networks of the PI3K/AKT and MAPK signaling cascades for regulating T. gondii-induced IL-23 and IL-12 secretion in human monocytic cells.