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      Norisoboldine, a natural aryl hydrocarbon receptor agonist, alleviates TNBS-induced colitis in mice, by inhibiting the activation of NLRP3 inflammasome

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          Abstract

          Although the etiology of inflammatory bowel disease is still uncertain, increasing evidence indicates that the excessive activation of NLRP3 inflammasome plays a major role. Norisoboldine (NOR), an alkaloid isolated from Radix Linderae, has previously been demonstrated to inhibit inflammation and IL-1 β production. The present study was to examine the effect of NOR on colitis and the underlying mechanism related to NLRP3 inflammasome activation. Our results showed that NOR alleviated colitis symptom in mice induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Moreover, it significantly reduced expressions of cleaved IL-1 β, NLRP3 and cleaved Caspase-1 but not ASC in colons of mice. In THP-1 cells, NOR suppressed the expressions of NLRP3, cleaved Caspase-1 and cleaved IL-1 β but not ASC induced by lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Furthermore, NOR could activate aryl hydrocarbon receptor (AhR) in THP-1 cells, inducing CYP1A1 mRNA expression, and promoting dissociation of AhR/HSP90 complexes, association of AhR and ARNT, AhR nuclear translocation, XRE reporter activity and binding activity of AhR/ARNT/XRE. Both siAhR and α-naphthoflavone (α-NF) markedly diminished the inhibition of NOR on NLRP3 inflammasome activation. In addition, NOR elevated Nrf2 level and reduced ROS level in LPS- and ATP-stimulated THP-1 cells, which was reversed by either siAhR or α-NF treatment. Finally, correlations between activation of AhR and attenuation of colitis, inhibition of NLRP3 inflammasome activation and up-regulation of Nrf2 level in colons were validated in mice with TNBS-induced colitis. Taken together, NOR ameliorated TNBS-induced colitis in mice through inhibiting NLRP3 inflammasome activation via regulating AhR/Nrf2/ROS signaling pathway.

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          Author and article information

          Journal
          CJNM
          Chinese Journal of Natural Medicines
          Elsevier
          1875-5364
          20 March 2018
          : 16
          : 3
          : 161-174
          Affiliations
          1Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China
          Author notes
          *Corresponding authors: WEI Zhi-Feng, Tel: 86-25-83271400, Fax: 86-25-85301528. E-mails: 1020132346@ 123456cpu.edu.cn ; DAI Yue, yuedaicpu@ 123456126.com

          ΔThese authors contributed equally to this work.

          These authors have no conflict of interest to declare.

          Article
          S1875-5364(18)30044-X
          10.1016/S1875-5364(18)30044-X
          29576052
          Copyright © 2018 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.
          Funding
          Funded by: Natural Science Foundation of Jiangsu Province of China
          Award ID: BK20140662
          Funded by: National Natural Science Foundation of China
          Award ID: 81503319
          This work was supported by the Natural Science Foundation of Jiangsu Province of China (No. BK20140662), and partially supported by the National Natural Science Foundation of China (No. 81503319) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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