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

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

SUBMITTER: Nie X 

PROVIDER: S-EPMC5498490 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature