Suppression of the TRIF-dependent signaling pathway of toll-like receptors by 4-oxo-4-(2-oxo-oxazolidin-3-yl)-but-2-enoic acid ethyl ester

Abstract

Toll-like receptors (TLRs) recognize molecular structures derived from microbes and initiate innate immunity. The stimulation of TLRs by microbial components triggers the activation of the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent major downstream signaling pathways. Previously, we synthesized a fumaryl oxazolidinone derivative, 4-oxo-4-(2-oxo-oxazolidin-3-yl)-but-2-enoic acid ethyl ester (OSL07), and demonstrated that it inhibits activation of nuclear factor kappa B (NF-?B) by inhibiting the TLR MyD88-dependent pathway. However, the effect of OSL07 on the TRIFdependent pathway remained unknown. Here, we examined the effect of OSL07 on signal transduction via the TLR TRIF-dependent pathway. OSL07 inhibited lipopolysaccharide- or polyinosinic-polycytidylic acid-induced interferon regulatory factor 3 activation and phosphorylation as well as interferon-inducible genes such as interferon inducible protein-10. All the results suggest that OSL07 can modulate TRIF-dependent signaling pathway of TLRs leading to decreased inflammatory gene expression.