AUTHOR=Qu Fufa , Xu Wenqian , Deng Zhangren , Xie Yifang , Tang Jianzhou , Chen Zhiguo , Luo Wenjie , Xiong Ding , Zhao Dafang , Fang Jiamei , Zhou Zhigang , Liu Zhen 

TITLE=Fish c-Jun N-Terminal Kinase (JNK) Pathway Is Involved in Bacterial MDP-Induced Intestinal Inflammation

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00459

DOI=10.3389/fimmu.2020.00459

ISSN=1664-3224

ABSTRACT=<p>The c-Jun NH<sub>2</sub>-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 (<italic>Ci</italic>JNK) pathway was identified, and its potential roles in bacterial muramyl dipeptide (MDP)-induced intestinal inflammation were investigated in <italic>Ctenopharyngodon idella</italic>. The present <italic>Ci</italic>JNK 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 (<italic>Aeromonas hydrophila</italic>) 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 <italic>Ci</italic>JNK could associate with <italic>Ci</italic>MKK4 and <italic>Ci</italic>MKK7 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 <italic>C. idella</italic>, which may provide new insight into the pathogenesis of inflammatory bowel disease.</p>