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

• Published in: Scientific reports 2017-07, Vol.7 (1), p.4738-10, Article 4738
• Main Authors: Nie, Xin, Chen, Shao-Ru, Wang, Kun, Peng, Yuran, Wang, Yi-Tao, Wang, Decai, Wang, Ying, Zhou, Guo-Chun
• Format: Article
• Language: English
• Subjects: 13; 13/21; 13/95; 38; 631/250/516/1909; 631/92/2783; 96; 96/95; 96/98; Animal models; Cytokines; Humanities and Social Sciences; Innate immunity; Interferon; Lipopolysaccharides; multidisciplinary; NF-κB protein; Nuclear transport; Phosphorylation; Rodents; Science; Science (multidisciplinary); Signal transduction; TLR3 protein; TLR4 protein; TLR9 protein; Toll-like receptors; Translocation; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-04673-x

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.