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Int Immunopharmacol. 2019 Feb;67:211-219. doi: 10.1016/j.intimp.2018.12.017. Epub 2018 Dec 15.

Rapamycin ameliorates lipopolysaccharide-induced acute lung injury by inhibiting IL-1β and IL-18 production.

Author information

1
Department of Respiratory Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China.
2
Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing 100029, China; National Clinical Research Center for Respiratory Diseases, Beijing 100029, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100069, China.
3
Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
4
Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: zhxlwl@ccmu.edu.cn.
5
Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China; Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing 100029, China; National Clinical Research Center for Respiratory Diseases, Beijing 100029, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100069, China; Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China. Electronic address: cyh-birm@263.net.

Abstract

Interleukin (IL)-1β and IL-18 play central and detrimental roles in the development of acute lung injury (ALI), and mammalian target of rapamycin (mTOR) is involved in regulating IL-1β and IL-18 production. However, it is not clear whether the mTOR specific inhibitor rapamycin can attenuate lipopolysaccharide (LPS)-induced ALI by modulating IL-1β and IL-18 production. In this study, we found that rapamycin ameliorated LPS-induced ALI by inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated IL-1β and IL-18 secretion. Mechanistically, elevated autophagy and decreased nuclear factor (NF)-κB activation were associated with downregulated IL-1β and IL-18. Moreover, rapamycin reduced leukocyte infiltration in the lung tissue and bronchoalveolar lavage fluid (BALF), and contributed to the alleviation of LPS-induced ALI. Consistently, rapamycin also significantly inhibited IL-1β and IL-18 production by RAW264.7 cells via increased autophagy and decreased NF-κB signaling in vitro. Our results demonstrated that rapamycin protects mice against LPS-induced ALI partly by inhibiting the production and secretion of IL-1β and IL-18. mTOR and rapamycin might represent an appropriate therapeutic target and strategy for preventing ALI induced by LPS.

KEYWORDS:

Acute lung injury; Autophagy; IL-18; IL-1β; NF-κB; mTOR

PMID:
30557824
DOI:
10.1016/j.intimp.2018.12.017
[Indexed for MEDLINE]

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