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

doi:10.1002/1873-3468.12768

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

PHA - Pharmacy

Tohoku University

Research output: Contribution to journal › Article › peer-review

4 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 language	English
Pages (from-to)	2406-2416
Number of pages	11
Journal	FEBS Letters
Volume	591
Issue number	16
DOIs	https://doi.org/10.1002/1873-3468.12768
Publication status	Published - 2017 Aug

Keywords

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

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10.1002/1873-3468.12768

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Tsukamoto, H., Yamagata, Y., Ukai, I., Takeuchi, S., Okubo, M., Kobayashi, Y., Kozakai, S., Kubota, K., Mumasaki, M., Kanemitsu, Y., Matsumoto, Y., & Tomioka, Y. (2017). An inhibitory epitope of human Toll-like receptor 4 resides on leucine-rich repeat 13 and is recognized by a monoclonal antibody. FEBS Letters, 591(16), 2406-2416. https://doi.org/10.1002/1873-3468.12768

@article{cb6649fa71e44a9dabde3901be29a343,

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

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.",

keywords = "epitope, inhibitory monoclonal antibody, leucine-rich repeat, lipopolysaccharide, MD-2, Toll-like receptor 4",

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

note = "Funding Information: This work was supported in part by the a JSPS KAKENHI (grant number 24790112 to HT) and grants from the Takeda Science Foundation, the Ichiro Kanehara Foundation, the Research Foundation for Pharmaceutical Sciences, and the Tokyo Biochemical Research Foundation (all to HT). Publisher Copyright: {\textcopyright} 2017 Federation of European Biochemical Societies",

year = "2017",

month = aug,

doi = "10.1002/1873-3468.12768",

language = "English",

volume = "591",

pages = "2406--2416",

journal = "FEBS Letters",

issn = "0014-5793",

publisher = "Wiley-Blackwell",

number = "16",

}

Tsukamoto, H, Yamagata, Y, Ukai, I, Takeuchi, S, Okubo, M, Kobayashi, Y, Kozakai, S, Kubota, K, Mumasaki, M, Kanemitsu, Y, Matsumoto, Y & Tomioka, Y 2017, 'An inhibitory epitope of human Toll-like receptor 4 resides on leucine-rich repeat 13 and is recognized by a monoclonal antibody', FEBS Letters, vol. 591, no. 16, pp. 2406-2416. https://doi.org/10.1002/1873-3468.12768

TY - JOUR

T1 - An inhibitory epitope of human Toll-like receptor 4 resides on leucine-rich repeat 13 and is recognized by a monoclonal antibody

AU - Tsukamoto, Hiroki

AU - Yamagata, Yuki

AU - Ukai, Ippo

AU - Takeuchi, Shino

AU - Okubo, Misaki

AU - Kobayashi, Yohei

AU - Kozakai, Sao

AU - Kubota, Kanae

AU - Mumasaki, Muneo

AU - Kanemitsu, Yoshitomi

AU - Matsumoto, Yotaro

AU - Tomioka, Yoshihisa

N1 - Funding Information: This work was supported in part by the a JSPS KAKENHI (grant number 24790112 to HT) and grants from the Takeda Science Foundation, the Ichiro Kanehara Foundation, the Research Foundation for Pharmaceutical Sciences, and the Tokyo Biochemical Research Foundation (all to HT). Publisher Copyright: © 2017 Federation of European Biochemical Societies

PY - 2017/8

Y1 - 2017/8

N2 - 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.

AB - 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.

KW - epitope

KW - inhibitory monoclonal antibody

KW - leucine-rich repeat

KW - lipopolysaccharide

KW - MD-2

KW - Toll-like receptor 4

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U2 - 10.1002/1873-3468.12768

DO - 10.1002/1873-3468.12768

M3 - Article

C2 - 28741733

AN - SCOPUS:85028378949

SN - 0014-5793

VL - 591

SP - 2406

EP - 2416

JO - FEBS Letters

JF - FEBS Letters

IS - 16

ER -

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

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Keywords

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