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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Immunity and Disease Prevention Research » Research » Publications at this Location » Publication #227583
Title: Acrolein with an alpha, beta-unsaturated Carbonyl Group Inhibits LPS-induced Homodimerization of Toll-like Receptor 4

Author
item LEE, JEON-SOO - GWANGJU INSTITUTE SCI.TEC
item LEE, JOO YOUNG - GWANGJU INSTITUTE SCI.TEC
item LEE, MI YOUNG - SOONCHUNHYANG UNIV.KOREA
item Hwang, Daniel
item YOUN, HYUNG SUN - SOONCHUNHYANG UNIV. MED.

Submitted to: Trade Journal Publication
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/26/2007
Publication Date: 4/30/2008
Citation: Lee, J., Lee, J., Lee, M., Hwang, D.H., Youn, H. 2007. Acrolein with an alpha, beta-unsaturated Carbonyl Group Inhibits LPS-induced Homodimerization of Toll-like Receptor 4. Molecules and Cells. Vol.25, No2, 253-257.

Interpretive Summary: 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-kB (NF-kB) activation B is not'by lipopolysaccharide (LPS). The mechanism by which it inhibits NF-kB is not clear. The results of this study showed that Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of NF-kB 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.

Technical Abstract: Acrolein is a highly electrophilic a,ß-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-kB (NF-kB) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits NF-kB is not clear. Toll-like receptors (TLRs) play a key role in sensing microbial components and inducing innate immune responses, and LPSinduced 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 IFNß (TRIF)-dependent signaling pathways leading to activation of NF-kB and IFN-regulatory factor 3 (IRF3). Acrolein inhibited NF-kB and IRF3 activation by LPS, but it did not inhibit NF-kB or IRF3 activation by MyD88, inhibitor kB kinase (IKK)ß, TRIF, or TNFreceptor- associated factor family member-associated NF- kB activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of NF-kB 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.