Article

Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury

Authors: Yun-he Ding1, Yun-duan Song2, Ya-xian Wu1, Hui-qiong He1, Tian-hong Yu1, Yu-dong Hu1, De-peng Zhang1, Hong-chao Jiang1, Kai-kai Yu1, Xiao-zong Li2, Lei Sun1, Feng Qian1,3,4
1 Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
2 Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China
3 Research Center for Cancer Precision Medicine, Department of Medical Oncology, Bengbu Medical College, Bengbu 233003, China
4 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221004, China
Correspondence to: Feng Qian: fengqian@sjtu.edu.cn,
DOI: 10.1038/s41401-018-0061-3
Received: 4 March 2018
Accepted: 5 June 2018
Advance online: 16 July 2018

Abstract

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-α, IL-1β, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 μM). We further revealed that IAL suppressed LPS-induced NF-κB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-κB, 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.
Keywords: isoalantolactone; lipopolysaccharide; TRAF6 ubiquitination; macrophage; acute lung injury

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