1. Academic Validation
  2. Attenuation of Innate Immunity by Andrographolide Derivatives Through NF-κB Signaling Pathway

Attenuation of Innate Immunity by Andrographolide Derivatives Through NF-κB Signaling Pathway

  • Sci Rep. 2017 Jul 5;7(1):4738. doi: 10.1038/s41598-017-04673-x.
Xin Nie 1 Shao-Ru Chen 2 Kun Wang 1 Yuran Peng 1 Yi-Tao Wang 2 Decai Wang 1 Ying Wang 3 Guo-Chun Zhou 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, Jiangsu, 211816, China.
  • 2 State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR, China.
  • 3 State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR, China. emilyywang@umac.mo.
  • 4 School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, Jiangsu, 211816, China. gczhou@njtech.edu.cn.
Abstract

Andrographolide derivatives or analogs exhibit potent anti-inflammatory effects in several disease models through NF-κB activity. In this study, we synthesized different andrographolide derivatives and investigated their effects on the Toll-like Receptor (TLR)-induced production of pro-inflammatory cytokines. Among these compounds, 3b, 5a, and 5b inhibited both TNF-α/NF-κB and TLR4/NF-κB signaling pathways. Treatment with compounds 3b, 5a, and 5b and their structural analogs, 3a and 6b, suppressed the expression of pro-inflammatory cytokines upon the activation of TLR3 and TLR4 ligands. Compounds 3b and 5a, but not 3a, 5b, or 6b, inhibited the nuclear translocation of the NF-κB p65 subunit. Treatment with compounds 3b, 5a, 3a, 5b, and 6b attenuated the phosphorylation of p65 and IκBα. Compounds 6b suppressed the expression of the NF-κB p65 subunit. However, these compounds, except for 5b, did not affect the TLR9-induced NF-κB-independent production of the pro-inflammatory cytokines, TNF-α, and IFN-β. Compound 3b potentially protected mice from LPS-induced acute pulmonary inflammation through the inhibition of p65 phosphorylation and the decrease of serum pro-inflammatory cytokines and chemokine. Our study revealed a functional structure-activity relationship between andrographolide derivatives and innate immunity. We identified compound 3b as a potent immune suppressive agent with the potential to protect acute pulmonary Infection.

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