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.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China [81773741, 81401302, 81573438, 31741038, and 81373424], the National Key Research and Development Program of China (2017YFC0908500) and Research Grant for Health Science and Technology of Pudong Municipal Commission of Health and family Planning of Shanghai (Grant Number PW2017A-24).
Author contributions
FQ and YD designed the study and drafted the manuscript. YS and YW participated in the project design and animal experiments. YD and TY performed the experiments. HH, YH, DZ, HJ, KY, XL, and LS helped in data analysis and discussion.
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Ding, Yh., Song, Yd., Wu, Yx. et al. Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury. Acta Pharmacol Sin 40, 64–74 (2019). https://doi.org/10.1038/s41401-018-0061-3
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DOI: https://doi.org/10.1038/s41401-018-0061-3
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