PMID- 30013035 OWN - NLM STAT- MEDLINE DCOM- 20190326 LR - 20201209 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 40 IP - 1 DP - 2019 Jan TI - Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury. PG - 64-74 LID - 10.1038/s41401-018-0061-3 [doi] AB - Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-alpha, IL-1beta, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 muM). We further revealed that IAL suppressed LPS-induced NF-kappaB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-kappaB, contributed to the anti-inflammatory effects of IAL. ALI was induced in mice by intratracheal injection of LPS (5 mg/kg). Administration of IAL (20 mg/kg, i.p.) significantly suppressed pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro-inflammatory cytokine expression. Our results demonstrate that IAL is a potential therapeutic reagent against inflammation and ALI. FAU - Ding, Yun-He AU - Ding YH AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. FAU - Song, Yun-Duan AU - Song YD AD - Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University, Shanghai, 201399, China. FAU - Wu, Ya-Xian AU - Wu YX AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. FAU - He, Hui-Qiong AU - He HQ AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. FAU - Yu, Tian-Hong AU - Yu TH AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. FAU - Hu, Yu-Dong AU - Hu YD AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. FAU - Zhang, De-Peng AU - Zhang DP AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. FAU - Jiang, Hong-Chao AU - Jiang HC AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. FAU - Yu, Kai-Kai AU - Yu KK AD - Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. FAU - Li, Xiao-Zong AU - Li XZ AD - Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University, Shanghai, 201399, 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, 200240, 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, 200240, China. fengqian@sjtu.edu.cn. AD - Research Center for Cancer Precision Medicine, Department of Medical Oncology, Bengbu Medical College, Bengbu, 233003, China. fengqian@sjtu.edu.cn. AD - Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, 221004, China. fengqian@sjtu.edu.cn. LA - eng PT - Journal Article DEP - 20180716 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Cytokines) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B p50 Subunit) RN - 0 (Sesquiterpenes) RN - 0 (TNF Receptor-Associated Factor 6) RN - 0 (Tifab protein, human) RN - 147257-52-1 (Nfkb1 protein, mouse) RN - BYH07P620U (isoalantolactone) SB - IM MH - Acute Lung Injury/chemically induced/*drug therapy/pathology MH - Animals MH - Anti-Inflammatory Agents/*therapeutic use MH - Cytokines/metabolism MH - HEK293 Cells MH - Humans MH - Inflammation/*drug therapy MH - Intracellular Signaling Peptides and Proteins MH - Lipopolysaccharides MH - Lung/pathology MH - Male MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - NF-kappa B p50 Subunit/metabolism MH - Sesquiterpenes/*therapeutic use MH - Signal Transduction/drug effects MH - TNF Receptor-Associated Factor 6/*metabolism MH - Ubiquitination/*drug effects PMC - PMC6318348 OTO - NOTNLM OT - TRAF6 ubiquitination OT - acute lung injury OT - isoalantolactone OT - lipopolysaccharide OT - macrophage COIS- The authors declare no competing interests. EDAT- 2018/07/18 06:00 MHDA- 2019/03/27 06:00 PMCR- 2020/01/01 CRDT- 2018/07/18 06:00 PHST- 2018/03/04 00:00 [received] PHST- 2018/06/05 00:00 [accepted] PHST- 2018/07/18 06:00 [pubmed] PHST- 2019/03/27 06:00 [medline] PHST- 2018/07/18 06:00 [entrez] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.1038/s41401-018-0061-3 [pii] AID - 61 [pii] AID - 10.1038/s41401-018-0061-3 [doi] PST - ppublish SO - Acta Pharmacol Sin. 2019 Jan;40(1):64-74. doi: 10.1038/s41401-018-0061-3. Epub 2018 Jul 16.