Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel (Nat Immunol, 2010, 11:814-819)

報告日期: 2010/10/19
報告時間: 17:10/18:00
報告學生: 陳逸純
講評老師: 蔡佩珍

Full text:

Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel

Marc Schmidt, et al. 2010. Nature Immunology. 11, 814 - 819


Speaker: Yi Chun Chen (陳逸純)

Commentator: Dr. Tsai, Pei-Jane (蔡佩珍教授)

Time: 17:00~18:00, Oct 18, 2010

Place: Room 602




Allergies to nickel (Ni2+) are the most frequent cause of contact hypersensitivity (CHS) in industrialized countries. Previous work has shown that Ni2+ induces expression of proinflammatory genes, a process dependent on induction of NF-κB activation(1), and authors suggests that Ni2+ may interact with Toll-like receptor (TLR) signal transduction. In this study they show that Ni2+ induced an inflammatory response by directly activating human Toll-like receptor 4 (TLR4), and is independent of LPS but requires both human TLR4 and human MD2. But progress toward understanding Ni2+ allergy has been hindered by the lack of mouse models - because mice do not readily develop Ni2+ hypersensitivity(2). To identify the difference both human and mouse TLR4, the authors identified the specific region of human TLR4 that is responsible for Ni2+ responses, and focused on two nonconserved histidine residues(His456 and His458) present in this region. Mutagenesis studies demonstrated that these two histidines are together required for Ni2+-induced NF-κB activation. To prove the in vivo relevance of their findings, the authors transgenically expressed human TLR4 in Tlr4/ mice and demonstrated that bone marrow–derived macrophages from the transgenic mice gained responsiveness to Ni2+. Additionally, these human TLR4–transgenic mice were readily susceptible to induction of experimental allergic contact hypersensitivity induced by Ni2+. These results clearly identify Ni2+ as an inorganic activator of the TLR system ,and the authors have not only identified TLR4 as the Ni2+ receptor but also elucidated the Ni2+ binding site, and they present a model whereby Ni2+ is capable of activating TLR4 homodimer formation, leading to signal transduction and production of proinflammatory cytokines.




1.    Goebeler, M. et al .1995.Activation of nuclear factor-kB and gene expression in human endothelial cells by the common haptens nickel and cobalt. J. Immunol. 155, 2459–2467.

2.    Artik, S. et al . 1999. Nickel allergy in mice: enhanced sensitization capacity of nickel at higher oxidation states. J. Immunol. 163, 1143–1152.