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

作者：Nie, Xin; Chen, Shao-Ru; Wang, Kun; Peng, Yuran; Wang, Yi-Tao; Wang, Decai; Wang, Ying; Zhou, Guo-Chun^*

来源：Scientific Reports, 2017, 7(1): 4738.

DOI：10.1038/s41598-017-04673-x

• X RECEPTOR
• CELLS
• ACTIVATION
• ANGIOGENESIS
• INFLAMMATION
• RECOGNITION
• MODULATION
• PANICULATA
• APOPTOSIS
• FIBROSIS

Andrographolide derivatives or analogs exhibit potent anti-inflammatory effects in several disease models through NF-kappa B 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-alpha/NF-kappa B and TLR4/NF-kappa B 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-kappa B p65 subunit. Treatment with compounds 3b, 5a, 3a, 5b, and 6b attenuated the phosphorylation of p65 and I kappa B alpha. Compounds 6b suppressed the expression of the NF-kappa B p65 subunit. However, these compounds, except for 5b, did not affect the TLR9-induced NF-kappa B-independent production of the pro-inflammatory cytokines, TNF-alpha, and IFN-beta. 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.

• 出版日期2017-7-5
• 单位澳门大学