Inhibition of homodimerization of Toll-like receptor 4 by 4-oxo-4-(2-oxo-oxazolidin-3-yl)-but-2-enoic acid ethyl ester

Toll-like receptors (TLRs) recognize molecular structures derived from microbes and initiate innate immunity. The stimulation of TLR4 by lipopolysaccharide (LPS) triggers the activation of the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (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-kappa B) by inhibiting the MyD88-dependent pathway of TLRs. TLR4 and the downstream signaling components are good therapeutic targets for many chronic inflammatory diseases. Here, it is investigated whether OSL07 modulates TLR4 downstream signaling pathways and what anti-inflammatory target in TLR4 signaling is regulated by OSL07. OSL07 inhibited LPS-induced NF-kappa B and interferon regulatory factor 3 activation by targeting TLR4 dimerization. These results suggest that OSL07 can modulate TLR4 signaling pathway leading to decreased inflammatory gene expression. (C) 2010 Elsevier B.V. All rights reserved.