Acrolein with an alpha, beta-unsaturated carbonyl group inhibits LPS-induced homodimerization of toll-like receptor 4

Mol Cells. 2008 Apr 30;25(2):253-7. Epub 2008 Mar 31.


Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde present in a number of environmental sources, especially cigarette smoke. It reacts strongly with the thiol groups of cysteine residues by Michael addition and has been reported to inhibit nuclear factor-kappaB (NF-kappaB) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits NF-kappaB is not clear. Toll-like receptors (TLRs) play a key role in sensing microbial components and inducing innate immune responses, and LPS-induced dimerization of TLR4 is required for activation of downstream signaling pathways. Thus, dimerization of TLR4 may be one of the first events involved in activating TLR4-mediated signaling pathways. Stimulation of TLR4 by LPS activates both myeloid differential factor 88 (MyD88)- and TIR domain-containing adapter inducing IFNbeta(TRIF)-dependent signaling pathways leading to activation of NF-kappaB and IFN-regulatory factor 3 (IRF3). Acrolein inhibited NF-kappaB and IRF3 activation by LPS, but it did not inhibit NF-kappaB or IRF3 activation by MyD88, inhibitor kappaB kinase (IKK)beta, TRIF, or TNF-receptor-associated factor family member-associated NF-kappaB activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of NF-kappaB and IRF3 activation. These results suggest that activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain chemicals with a structural motif that enables Michael addition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / chemistry*
  • Acrolein / pharmacology*
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Cell Line
  • Dimerization
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Toll-Like Receptor 4 / metabolism*


  • Adaptor Proteins, Vesicular Transport
  • Interferon Regulatory Factor-3
  • Lipopolysaccharides
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • TICAM-1 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Acrolein