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

Jeon Soo Lee, Joo Young Lee, Mi Young Lee, Daniel H. Hwang, Hyung Sun Youn

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Acrolein is a highly electrophilic α,β-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-κB (NF-κB) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits NF-κB 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 IFNβ (TRIF)-dependent signaling pathways leading to activation of NF-κB and IFN-regulatory factor 3 (IRF3). Acrolein inhibited NF-κB and IRF3 activation by LPS, but it did not inhibit NF-κB or IRF3 activation by MyD88, inhibitor κB kinase (IKK)β, TRIF, or TNF-receptor-associated factor family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of NF-κB 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.

Original languageEnglish (US)
Pages (from-to)253-257
Number of pages5
JournalMolecules and Cells
Volume25
Issue number2
StatePublished - Apr 30 2008

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Keywords

  • Acrolein
  • Dimerization
  • IRF3
  • LPS
  • Michael addition
  • NF-κB
  • Toll-like receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Lee, J. S., Lee, J. Y., Lee, M. Y., Hwang, D. H., & Youn, H. S. (2008). Acrolein with an α,β-unsaturated carbonyl group inhibits LPS-induced homodimerization of toll-like receptor 4. Molecules and Cells, 25(2), 253-257.