p38 mitogen-activated protein kinases (MAPKs) are involved in intestinal immune response to bacterial muramyl dipeptide challenge in Ctenopharyngodon idella
p38 mitogen-activated protein kinases (MAPKs) are involved in intestinal immune response to bacterial muramyl dipeptide challenge in Ctenopharyngodon idella
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p38 丝裂原激活蛋白激酶 (MAPK) 参与草鱼细菌胞壁酰二肽攻击的肠道免疫反应
DOI：
10.1016/j.molimm.2019.12.007
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发表时间：
2020
影响因子：
3.6
通讯作者：
Zhen Liu
中科院分区：
文献类型：
--
作者：
Yu;ong Sun;Wenqian Xu;Die Li;Hui Zhou;Fufa Qu;Shenping Cao;Jianzhou Tang;Yonghua Zhou;Zhimin He;Hang Li;Zhigang Zhou;Zhen Liu
p38丝裂原活化蛋白激酶（MAPKs）是先天免疫途径中必不可少的细胞质信号分子，在宿主对病原挑战的免疫防御反应中起着至关重要的作用。本研究首次从草鱼tenopharyngodon idella中分离到两个鱼类p38基因（Cip38α和cip38 β）。与其他已报道的p38MAPKs类似，cip38 α和cip38 β在丝氨酸/苏氨酸蛋白激酶（S_TKc）结构域中含有一个保守的磷酸化基序（Thr-Gly-Tyr， TGY）和一个底物结合位点（Ala-Thr-Arg-Trp， ATRW）。表达谱分析显示，cip38 α和cip38 β mrna在c的所有组织和发育阶段均广泛表达。idella。此外，体内注射实验直接揭示了cip38 α和cip38 β对亲水气单胞菌和muramyl dipeptide （MDP）的侵袭表现出较强的反应性，其在草鱼肠道中的表达水平显著上调。此外，mdp诱导的肠道炎症因子（TNF-α和IL-15）和抗菌肽（β-防御素）的表达水平被p38mapk特异性抑制剂SB203580显著抑制。此外，营养二肽肌肽和Ala-Gln可显著抑制细菌mdp诱导的草鱼肠道p38MAPK通路基因和炎症因子的表达。最后，过表达分析表明，cip38 α和cip38 β可以通过与cimkk6相互作用，作为有效的激活剂调节AP-1信号通路。总之，本研究为草鱼中存在功能性p38通路提供了实验证据，揭示了其参与硬骨鱼肠道对细菌攻击的免疫反应。
The p38 mitogen-activated protein kinases (MAPKs) are essential cytoplasmic signal molecules of innate immune pathways that play a vital role in host immune defense responses to pathogenic challenges. In this study, two fish p38 genes (Cip38α andCip38β) were characterized for the first time from the grass carpCtenopharyngodon idella. Similar to other reported p38MAPKs, bothCip38α andCip38β contained a conserved phosphorylation motif (Thr-Gly-Tyr, TGY) and a substrate binding site (Ala-Thr-Arg-Trp, ATRW) in the serine/threonine protein kinase (S_TKc) domain. Expression profile analysis showed thatCip38α andCip38β mRNAs were broadly expressed in all of the examined tissues and developmental stages ofC. idella. In addition, in vivo injection experiments directly revealed thatCip38α andCip38β showed strong responsiveness toAeromonas hydrophilaand muramyl dipeptide (MDP) challenges, and their expression levels were significantly upregulated in the intestine of grass carp. Additionally, the MDP-induced expression levels of intestinal inflammatory cytokines (TNF-α and IL-15) and an antimicrobial peptide (β-defensin) were significantly inhibited by the p38MAPK-specific inhibitor SB203580. Moreover, the nutritional dipeptide carnosine and Ala-Gln were found to significantly suppress the bacterial MDP-induced expression of p38MAPK pathway genes and inflammatory cytokines in the intestine of grass carp. Finally, overexpression analysis demonstrated thatCip38α andCip38β could act as efficient activators in the regulation of AP-1 signaling pathways through interaction withCiMKK6. Altogether, this study provided experimental evidence of the presence of a functional p38 pathway in grass carp, which revealed its involvement in the intestinal immune response to bacterial challenges in bony fish.