PMID- 29770701 OWN - NLM STAT- MEDLINE DCOM- 20190702 LR - 20211204 IS - 1522-1504 (Electronic) IS - 1040-0605 (Linking) VI - 315 IP - 3 DP - 2018 Sep 1 TI - MK2 mediates macrophage activation and acute lung injury by regulating let-7e miRNA. PG - L371-L381 LID - 10.1152/ajplung.00019.2018 [doi] AB - MAPK-activated protein kinase 2 (MK2) plays a critical role in the development of inflammation. However, the modulatory mechanisms in macrophage activation and acute lung injury (ALI) have not been completely defined. Here, we reported that MK2-deficient mice (MK2(-/-)) protected against sepsis-induced ALI. In response to lipopolysaccharide (LPS) challenge, MK2(-/-) mice and myeloid cell-specific MK2 conditional knockout mice (MK2(Lyz2-KO)) exhibited attenuated inflammatory response, especially producing fewer amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and macrophage inflammatory protein 2 (MIP-2). LPS treatment in vitro resulted in reduced cytokine expression in MK2(-/-) bone marrow-derived macrophages (BMDMs). Furthermore, we found that LPS-induced microRNA lethal-7e ( let-7e) expression was significantly increased in MK2(-/-) macrophages. Transfection of let-7e antagomirs into MK2(-/-) BMDM rescued LPS-induced expression of TNF-alpha, IL-6, and MIP-2. In contrast, transfection of let-7e mimics into MK2(+/+)BMDM decreased cytokine expression. Meanwhile, LPS-induced phosphorylation of cAMP response element-binding (CREB) protein, a substrate of MK2, was downregulated in MK2(-/-) BMDMs. Lin28, an inhibitory molecule of let-7, was significantly reduced in MK2(-/-) macrophages. Our results suggested that MK2 boosts LPS-induced macrophage activation and ALI via increasing activation of CREB and consequently, the expression of Lin28 and downregulation of let-7e. FAU - Wu, Yaxian AU - Wu Y AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. FAU - He, Huiqiong AU - He H AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. FAU - Ding, Yunhe AU - Ding Y AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. FAU - Liu, Sirui AU - Liu S AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. FAU - Zhang, Depeng AU - Zhang D AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. FAU - Wang, Jun AU - Wang J AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. FAU - Jiang, Hongchao AU - Jiang H AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. FAU - Zhang, Dan AU - Zhang D AD - Research Center for Cancer Precision Medicine, Department of Medical Oncology, Bengbu Medical College, Bengbu, Anhui , People's Republic of China. FAU - Sun, Lei AU - Sun L AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. FAU - Ye, Richard D AU - Ye RD AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. AD - Institute of Chinese Medical Sciences, University of Macau, Macau, People's Republic of China. FAU - Qian, Feng AU - Qian F AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University , Shanghai , People's Republic of China. AD - Research Center for Cancer Precision Medicine, Department of Medical Oncology, Bengbu Medical College, Bengbu, Anhui , People's Republic of China. AD - Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University , Xuzhou , People's Republic of China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180517 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (Creb1 protein, mouse) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Cytokines) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Lipopolysaccharides) RN - 0 (MicroRNAs) RN - 0 (mirnlet7 microRNA, mouse) RN - EC 2.7.1.- (MAP-kinase-activated kinase 2) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Acute Lung Injury/etiology/genetics/*metabolism/pathology MH - Animals MH - Cyclic AMP Response Element-Binding Protein/genetics/metabolism MH - Cytokines/genetics/metabolism MH - Down-Regulation/drug effects/genetics MH - Intracellular Signaling Peptides and Proteins/genetics/*metabolism MH - Lipopolysaccharides/toxicity MH - *Macrophage Activation MH - Macrophages/*metabolism/pathology MH - Mice MH - Mice, Knockout MH - MicroRNAs/*biosynthesis/genetics MH - Phosphorylation/drug effects/genetics MH - Protein Serine-Threonine Kinases/genetics/*metabolism MH - *Sepsis/complications/genetics/metabolism/pathology OTO - NOTNLM OT - MAPK-activated protein kinase 2 OT - MK2 OT - acute lung injury OT - let-7e OT - lipopolysaccharides OT - macrophage OT - miRNA EDAT- 2018/05/18 06:00 MHDA- 2019/07/03 06:00 CRDT- 2018/05/18 06:00 PHST- 2018/05/18 06:00 [pubmed] PHST- 2019/07/03 06:00 [medline] PHST- 2018/05/18 06:00 [entrez] AID - 10.1152/ajplung.00019.2018 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2018 Sep 1;315(3):L371-L381. doi: 10.1152/ajplung.00019.2018. Epub 2018 May 17.