LY294002 inhibits TLR3/4-mediated IFN-β production via inhibition of IRF3 activation with a PI3K-independent mechanism

TLR3 and TLR4 utilize adaptor TRIF to activate interferon regulatory factor 3 (IRF3), resulting in interferon β (IFN-β) production to mediate anti-viral infection. In this report, we analyzed the effect of two known phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin on LPS- and poly(I:C)-induced IFN-β production in peritoneal macrophages. LY294002 inhibited LPS- and poly(I:C)-induced IFN-β transcription and secretion. In contrast, wortmannin could not inhibit IFN-β production. Furthermore, IRF3 transcriptional activation and binding to IFN-β promoter were found to be inhibited by LY294002. Therefore, our findings demonstrate LY294002 negatively regulates LPS- and poly(I:C)-induced IFN-β production through inhibition of IRF3 activation in a PI3K-independent manner.

► LY294002 and wortmannin have opposite functions on LPS- and poly(I:C)-induced IFN-β production.
► LY294002 inhibits LPS- and poly(I:C)-induced IFN-β transcription and secretion in a PI3K-independent manner.
► LY294002 inhibits TLR-induced IFN-β production through inhibition of IRF3 activation and IRF3 DNA binding.