Acrolein with an α,β-unsaturated Carbonyl Group Inhibits LPS-induced Homodimerization of Toll-like Receptor 4

  • Lee, Jeon-Soo (Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University) ;
  • Lee, Joo Young (Department of Life Science, Gwangju Institute of Science and Technology) ;
  • Lee, Mi Young (Department of Medical Biotechnology, College of Medical Sciences, Soonchunhyang University) ;
  • Hwang, Daniel H. (USDA, ARS, Western Human Nutrition Research Center, and Department of Nutrition, University of California) ;
  • Youn, Hyung Sun (Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University)
  • Received : 2007.08.20
  • Accepted : 2007.10.26
  • Published : 2008.04.30

Abstract

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 $factor-{\kappa}B$ ($NF-{\kappa}B$) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits $NF-{\kappa}B$ 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 $IFN{\beta}$ (TRIF)-dependent signaling pathways leading to activation of $NF-{\kappa}B$ and IFN-regulatory factor 3 (IRF3). Acrolein inhibited $NF-{\kappa}B$ and IRF3 activation by LPS, but it did not inhibit $NF-{\kappa}B$ or IRF3 activation by MyD88, inhibitor ${\kappa}B$ kinase $(IKK){\beta}$, TRIF, or TNF-receptor-associated factor family member-associated $NF-{\kappa}B$ activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of $NF-{\kappa}B$ 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.

Keywords

Acrolein;Dimerization;LPS;Michael Addition;NF-κB;IRF3;Toll-like Receptor

Acknowledgement

Supported by : Soonchunhyang University

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