Fish c-Jun N-Terminal Kinase (JNK) Pathway Is Involved in Bacterial MDP-Induced Intestinal Inflammation
Fish c-Jun N-Terminal Kinase (JNK) Pathway Is Involved in Bacterial MDP-Induced Intestinal Inflammation
复制标题
鱼 c-Jun N 末端激酶 (JNK) 通路参与细菌 MDP 诱导的肠道炎症
DOI：
10.3389/fimmu.2020.00459
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Zhen Liu
中科院分区：
文献类型：
--
作者：
Fufa Qu;Wenqian Xu;Zhangren Deng;Yifang Xie;Jianzhou Tang;Zhiguo Chen;Wenjie Luo;Ding Xiong;Dafang Zhao;Jiamei Fang;Zhigang Zhou;Zhen Liu
c-Jun NH 2-末端激酶（JNK）是一个进化上保守的丝氨酸/苏氨酸蛋白激酶家族，在从昆虫到哺乳动物的物种的病理过程中发挥关键作用。然而，JNKs在细菌诱导的肠道炎症中的功能仍然知之甚少。在这项研究中，鱼JNK（CiJNK）的途径，并在细菌胞壁酰二肽（MDP）诱导的肠道炎症的潜在作用进行了研究。该基因在丝氨酸/苏氨酸蛋白激酶（S_TKc）结构域具有保守的双磷酸化基序（TPY），在其5′端侧翼区含有多个潜在的免疫相关转录因子结合位点，包括核因子κ B（NF-κB）、激活蛋白1（AP-1）和下游转录信号转导和激活因子3（STAT 3）。定量实时PCR结果显示，JNK途径基因在肠道中的mRNA水平显着上调后的挑战与细菌病原体（气单胞菌）和MDP在时间依赖性的方式。此外，JNK信号通路还参与调节草鱼肠道中MDP诱导的炎性细胞因子（IL-6、IL-8和TNF-α）的表达水平。此外，营养性二肽肌肽和Ala-Gln可通过调节JNK通路基因和炎症细胞因子的表达，有效减轻MDP诱导的草鱼肠道炎症反应。最后，荧光显微镜和双报告基因分析表明，CiJNK可以与参与AP-1信号通路调节的CiMKK 4和CiMKK 7缔合。总之，这些结果提供了第一个实验证明，JNK信号通路参与了肠道免疫反应，以MDP的挑战，在C。idella，这可能为炎症性肠病的发病机制提供新的见解。
The c-Jun NH2-terminal kinases (JNKs) are an evolutionarily conserved family of serine/threonine protein kinases that play critical roles in the pathological process in species ranging from insects to mammals. However, the function of JNKs in bacteria-induced intestinal inflammation is still poorly understood. In this study, a fish JNK (CiJNK) pathway was identified, and its potential roles in bacterial muramyl dipeptide (MDP)-induced intestinal inflammation were investigated in Ctenopharyngodon idella. The present CiJNK was found to possess a conserved dual phosphorylation motif (TPY) in a serine/threonine protein kinase (S_TKc) domain and to contain several potential immune-related transcription factor binding sites, including nuclear factor kappa B (NF-κB), activating protein 1 (AP-1), and signal transducer and activator of downstream transcription 3 (STAT3), in its 5′ flanking regions. Quantitative real-time PCR results revealed that the mRNA levels of the JNK pathway genes in the intestine were significantly upregulated after challenge with a bacterial pathogen (Aeromonas hydrophila) and MDP in a time-dependent manner. Additionally, the JNK pathway was found to be involved in regulating the MDP-induced expression levels of inflammatory cytokines (IL-6, IL-8, and TNF-α) in the intestine of grass carp. Moreover, the nutritional dipeptide carnosine and Ala–Gln could effectively alleviate MDP-induced intestinal inflammation by regulating the intestinal expression of JNK pathway genes and inflammatory cytokines in grass carp. Finally, fluorescence microscopy and dual-reporter assays indicated that CiJNK could associate with CiMKK4 and CiMKK7 involved in the regulation of the AP-1 signaling pathway. Overall, these results provide the first experimental demonstration that the JNK signaling pathway is involved in the intestinal immune response to MDP challenge in C. idella, which may provide new insight into the pathogenesis of inflammatory bowel disease.