An inhibitory epitope of human Toll-like receptor 4 resides on leucine-rich repeat 13 and is recognized by a monoclonal antibody

Hiroki Tsukamoto, Yuki Yamagata, Ippo Ukai, Shino Takeuchi, Misaki Okubo, Yohei Kobayashi, Sao Kozakai, Kanae Kubota, Muneo Mumasaki, Yoshitomi Kanemitsu, Yotaro Matsumoto, Yoshihisa Tomioka

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Lipopolysaccharide (LPS)-induced activation of Toll-like receptor 4 (TLR4) elicits the innate immune response and can trigger septic shock if excessive. Two antibodies (HT4 and HT52) inhibit LPS-induced human TLR4 activation via novel LPS binding-independent mechanisms. The HT52 epitope resides on leucine-rich repeat 2 (LRR2) and is a feature of many inhibitory antibodies; antigen specificity of HT4 does not reside in LRR2. Here, we identified an HT4 epitope on LRR13 located close to the TLR4 dimerization interface that plays a role in NFκB activation. HT4 and HT52 mutually enhanced TLR4 inhibition. LRR13 is a novel inhibitory epitope and may be useful for developing anti-TLR4 antibodies. Combination therapy with LRR2 and LRR13 may effectively inhibit TLR4 activation.

Original languageEnglish
Pages (from-to)2406-2416
Number of pages11
JournalFEBS Letters
Volume591
Issue number16
DOIs
Publication statusPublished - 2017 Aug

Keywords

  • MD-2
  • Toll-like receptor 4
  • epitope
  • inhibitory monoclonal antibody
  • leucine-rich repeat
  • lipopolysaccharide

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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