Alteration of Toll-like receptor 4 activation by 4-hydroxy-2-nonenal mediated by the suppression of receptor homodimerization. Export

@article{citeulike:5346607, abstract = {Toll-like receptors (TLRs) detect invading microbial pathogens and initiate immune responses as part of host defense mechanisms. They also respond to host-derived substances released from injured cells and tissues to ensure wound healing and tissue homeostasis. Dysregulation of TLRs increases the risk of chronic inflammatory diseases and immune disorders. Inflammatory events are often accompanied by oxidative stress, which generates lipid peroxidation products such as 4-hydroxy-2-nonenal (4-HNE). Therefore, we investigated if 4-HNE affects TLR activation. We found that 4-HNE blocked LPS (a TLR4 agonist)-induced activation of NFkappaB and IRF3 as well as expression of IFNbeta, IP-10, RANTES, and TNFalpha. To investigate the mechanism of inhibition by 4-HNE, we examined its effects on TLR4 dimerization, one of the initial steps in TLR4 activation. 4-HNE suppressed both ligand-induced and ligand-independent receptor dimerization. The thiol donors, DTT and NAC, prevented the inhibitory effects of 4-HNE on TLR4 dimerization, and LC-MS/MS analysis showed that 4-HNE formed adducts with cysteine residues of synthetic peptides derived from TLR4. These observations suggest that the reactivity of 4-HNE with sulfhydryl moieties is implicated in the inhibition of TLR4 activation. Furthermore, inhibition of TLR4 activation by 4-HNE resulted in down-regulation of the phagocytic activity of macrophages. Collectively, these results demonstrate that 4-HNE blocks TLR4-mediated macrophage activation, gene expression, and phagocytic functions, at least partly by suppressing receptor dimerization. They further suggest that 4-HNE influences innate immune responses at sites of infection and inflammation by inhibiting TLR4 activation.}, author = {Kim, Yoon Sun S. and Park, Zee Yong Y. and Kim, So Young Y. and Jeong, Eunshil and Lee, Joo Young Y.}, citeulike-article-id = {5346607}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.cbi.2009.07.009}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0009279709002786}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19627980}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19627980}, day = {10}, doi = {10.1016/j.cbi.2009.07.009}, issn = {1872-7786}, journal = {Chemico-biological interactions}, keywords = {tlr4}, month = {November}, number = {1}, pages = {59--66}, posted-at = {2009-10-31 16:52:06}, priority = {3}, title = {Alteration of Toll-like receptor 4 activation by 4-hydroxy-2-nonenal mediated by the suppression of receptor homodimerization.}, url = {http://dx.doi.org/10.1016/j.cbi.2009.07.009}, volume = {182}, year = {2009} }

TY - JOUR ID - citeulike:5346607 L3 - citeulike-article-id:5346607 N2 - Toll-like receptors (TLRs) detect invading microbial pathogens and initiate immune responses as part of host defense mechanisms. They also respond to host-derived substances released from injured cells and tissues to ensure wound healing and tissue homeostasis. Dysregulation of TLRs increases the risk of chronic inflammatory diseases and immune disorders. Inflammatory events are often accompanied by oxidative stress, which generates lipid peroxidation products such as 4-hydroxy-2-nonenal (4-HNE). Therefore, we investigated if 4-HNE affects TLR activation. We found that 4-HNE blocked LPS (a TLR4 agonist)-induced activation of NFkappaB and IRF3 as well as expression of IFNbeta, IP-10, RANTES, and TNFalpha. To investigate the mechanism of inhibition by 4-HNE, we examined its effects on TLR4 dimerization, one of the initial steps in TLR4 activation. 4-HNE suppressed both ligand-induced and ligand-independent receptor dimerization. The thiol donors, DTT and NAC, prevented the inhibitory effects of 4-HNE on TLR4 dimerization, and LC-MS/MS analysis showed that 4-HNE formed adducts with cysteine residues of synthetic peptides derived from TLR4. These observations suggest that the reactivity of 4-HNE with sulfhydryl moieties is implicated in the inhibition of TLR4 activation. Furthermore, inhibition of TLR4 activation by 4-HNE resulted in down-regulation of the phagocytic activity of macrophages. Collectively, these results demonstrate that 4-HNE blocks TLR4-mediated macrophage activation, gene expression, and phagocytic functions, at least partly by suppressing receptor dimerization. They further suggest that 4-HNE influences innate immune responses at sites of infection and inflammation by inhibiting TLR4 activation. IS - 1 JF - Chemico-biological interactions SN - 1872-7786 EP - 66 TI - Alteration of Toll-like receptor 4 activation by 4-hydroxy-2-nonenal mediated by the suppression of receptor homodimerization. VL - 182 SP - 59 KW - tlr4 AU - Kim, Yoon Sun AU - Park, Zee Yong AU - Kim, So Young AU - Jeong, Eunshil AU - Lee, Joo Young PY - 2009/11/10/ UR - http://dx.doi.org/10.1016/j.cbi.2009.07.009 ER -