PMID- 30541887 OWN - NLM STAT- MEDLINE DCOM- 20190322 LR - 20200309 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 115 IP - 52 DP - 2018 Dec 26 TI - Protein kinase p38alpha signaling in dendritic cells regulates colon inflammation and tumorigenesis. PG - E12313-E12322 LID - 10.1073/pnas.1814705115 [doi] AB - Dendritic cells (DCs) play pivotal roles in maintaining intestinal homeostasis, but how the DCs regulate diverse immune networks on homeostasis breakdown remains largely unknown. Here, we report that, in response to epithelial barrier disruption, colonic DCs regulate the differentiation of type 1 regulatory T (Tr1) cells through p38alpha-dependent IL-27 production to initiate an effective immune response. Deletion of p38alpha in DCs, but not in T cells, led to increased Tr1 and protected mice from dextran sodium sulfate-induced acute colitis and chronic colitis-associated colorectal cancer. We show that higher levels of IL-27 in p38alpha-deficient colonic cDC1s, but not cDC2s, were responsible for the increase of Tr1 cells. Moreover, p38alpha-dependent IL-27 enhanced IL-22 secretion from intestinal group 3 innate lymphoid cells and protected epithelial barrier function. In p38alpha-deficient DCs, the TAK1-MKK4/7-JNK-c-Jun axis was hyperactivated, leading to high IL-27 levels, and inhibition of the JNK-c-Jun axis suppressed IL-27 expression. ChIP assay revealed direct binding of c-Jun to the promoter of Il27p28, which was further enhanced in p38alpha-deficient DCs. In summary, here we identify a key role for p38alpha signaling in DCs in regulating intestinal inflammatory response and tumorigenesis, and our finding may provide targets for the treatment of inflammatory intestinal diseases. FAU - Zheng, Tingting AU - Zheng T AD - Shanghai Institute of Immunology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. FAU - Zhang, Baohua AU - Zhang B AD - Shanghai Institute of Immunology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. FAU - Chen, Ce AU - Chen C AD - Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808 Dongguan, China. FAU - Ma, Jingyu AU - Ma J AD - Shanghai Institute of Immunology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. FAU - Meng, Deyun AU - Meng D AD - Shanghai Institute of Immunology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. FAU - Huang, Jian AU - Huang J AD - Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808 Dongguan, China. FAU - Hu, Ran AU - Hu R AD - Shanghai Institute of Immunology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. FAU - Liu, Xinguang AU - Liu X AD - Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808 Dongguan, China. FAU - Otsu, Kinya AU - Otsu K AD - Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan. AD - School of Cardiovascular Medicine and Sciences, King's College London, SE59NU London, United Kingdom. FAU - Liu, Andrew C AU - Liu AC AUID- ORCID: 0000-0003-1927-0900 AD - Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610-0274. FAU - Li, Huabin AU - Li H AD - Allergy Center, Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye and ENT (Ears, Nose, and Throat) Hospital, Fudan University, 200031 Shanghai, China. FAU - Yin, Zhinan AU - Yin Z AD - The First Affiliated Hospital, Biomedical Translational Research Institute and Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, 510632 Guangzhou, China. FAU - Huang, Gonghua AU - Huang G AUID- ORCID: 0000-0003-1579-5478 AD - Shanghai Institute of Immunology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; gonghua.huang@shsmu.edu.cn. AD - Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808 Dongguan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181212 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Interleukin-27) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 14) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) RN - EC 2.7.11.25 (MAP kinase kinase kinase 7) SB - IM MH - Animals MH - Carcinogenesis MH - Colitis/*enzymology/genetics/immunology/pathology MH - Colon/enzymology/*immunology/pathology MH - Colorectal Neoplasms/*enzymology/genetics/immunology/pathology MH - Dendritic Cells/*enzymology/immunology MH - Female MH - Humans MH - Interleukin-27/genetics/immunology MH - Intestines/immunology/pathology MH - MAP Kinase Kinase Kinases/genetics/immunology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mitogen-Activated Protein Kinase 14/genetics/*immunology MH - T-Lymphocytes, Regulatory/immunology PMC - PMC6310843 OTO - NOTNLM OT - T cells OT - dendritic cells OT - inflammatory bowel disease OT - innate lymphoid cells OT - p38alpha MAPK COIS- The authors declare no conflict of interest. EDAT- 2018/12/14 06:00 MHDA- 2019/03/23 06:00 PMCR- 2019/06/12 CRDT- 2018/12/14 06:00 PHST- 2018/12/14 06:00 [pubmed] PHST- 2019/03/23 06:00 [medline] PHST- 2018/12/14 06:00 [entrez] PHST- 2019/06/12 00:00 [pmc-release] AID - 1814705115 [pii] AID - 201814705 [pii] AID - 10.1073/pnas.1814705115 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12313-E12322. doi: 10.1073/pnas.1814705115. Epub 2018 Dec 12.