An inhibitory epitope of human Toll‐like receptor 4 resides on leucine‐rich repeat 13 and is recognized by a monoclonal antibody
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 l...
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| Veröffentlicht in: | FEBS letters 2017-08, Vol.591 (16), p.2406-2416 |
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| creator | Tsukamoto, Hiroki Yamagata, Yuki Ukai, Ippo Takeuchi, Shino Okubo, Misaki Kobayashi, Yohei Kozakai, Sao Kubota, Kanae Mumasaki, Muneo Kanemitsu, Yoshitomi Matsumoto, Yotaro Tomioka, Yoshihisa |
| description | 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. |
| doi_str_mv | 10.1002/1873-3468.12768 |
| format | Article |
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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.</description><identifier>ISSN: 0014-5793</identifier><identifier>EISSN: 1873-3468</identifier><identifier>DOI: 10.1002/1873-3468.12768</identifier><identifier>PMID: 28741733</identifier><language>eng</language><publisher>England</publisher><subject>Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Antibodies, Monoclonal - immunology ; Cell Line ; epitope ; Epitopes - immunology ; Humans ; inhibitory monoclonal antibody ; leucine‐rich repeat ; lipopolysaccharide ; Lipopolysaccharides - pharmacology ; MD‐2 ; Mice ; Protein Multimerization ; Protein Structure, Quaternary ; Toll-Like Receptor 4 - chemistry ; Toll-Like Receptor 4 - immunology ; Toll-Like Receptor 4 - metabolism ; Toll‐like receptor 4</subject><ispartof>FEBS letters, 2017-08, Vol.591 (16), p.2406-2416</ispartof><rights>2017 Federation of European Biochemical Societies</rights><rights>2017 Federation of European Biochemical Societies.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4518-58340678c53c49021d392e42b238866e91afd97d5fddd4e8f9e4b68853ad670d3</citedby><cites>FETCH-LOGICAL-c4518-58340678c53c49021d392e42b238866e91afd97d5fddd4e8f9e4b68853ad670d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2F1873-3468.12768$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2F1873-3468.12768$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27903,27904,45553,45554,46387,46811</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28741733$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tsukamoto, Hiroki</creatorcontrib><creatorcontrib>Yamagata, Yuki</creatorcontrib><creatorcontrib>Ukai, Ippo</creatorcontrib><creatorcontrib>Takeuchi, Shino</creatorcontrib><creatorcontrib>Okubo, Misaki</creatorcontrib><creatorcontrib>Kobayashi, Yohei</creatorcontrib><creatorcontrib>Kozakai, Sao</creatorcontrib><creatorcontrib>Kubota, Kanae</creatorcontrib><creatorcontrib>Mumasaki, Muneo</creatorcontrib><creatorcontrib>Kanemitsu, Yoshitomi</creatorcontrib><creatorcontrib>Matsumoto, Yotaro</creatorcontrib><creatorcontrib>Tomioka, Yoshihisa</creatorcontrib><title>An inhibitory epitope of human Toll‐like receptor 4 resides on leucine‐rich repeat 13 and is recognized by a monoclonal antibody</title><title>FEBS letters</title><addtitle>FEBS Lett</addtitle><description>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.</description><subject>Amino Acid Motifs</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Cell Line</subject><subject>epitope</subject><subject>Epitopes - immunology</subject><subject>Humans</subject><subject>inhibitory monoclonal antibody</subject><subject>leucine‐rich repeat</subject><subject>lipopolysaccharide</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>MD‐2</subject><subject>Mice</subject><subject>Protein Multimerization</subject><subject>Protein Structure, Quaternary</subject><subject>Toll-Like Receptor 4 - chemistry</subject><subject>Toll-Like Receptor 4 - immunology</subject><subject>Toll-Like Receptor 4 - metabolism</subject><subject>Toll‐like receptor 4</subject><issn>0014-5793</issn><issn>1873-3468</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkLtuFDEUhi0EIkuSmg65pJnEtxnbZYhyQYpEE2rLY59hDR57GO8IDRVFHoBn5EniZUNaqnP7zl98CL2l5IwSws6pkrzholNnlMlOvUCb581LtCGEiqaVmh-hN6V8JXVWVL9GR0xJQSXnG_RwkXBI29CHXZ5XDFOtE-A84O0y2oTvc4x_fv2O4RvgGRxMFcOitiV4KDgnHGFxIUGF5uC29TKB3WHKsU0eh7L_yl9S-Ake9yu2eMwpu5iTjZXYhT779QS9GmwscPpUj9Hn66v7y9vm7tPNx8uLu8aJlqqmVVyQTirXcic0YdRzzUCwnnGlug40tYPX0reD916AGjSIvlOq5dZ3knh-jN4fcqc5f1-g7MwYioMYbYK8FEM145RIzUhFzw-om3MpMwxmmsNo59VQYvbqzV602Ys2f9XXj3dP4Us_gn_m_7muQHcAfoQI6__yzPXVB3ZIfgTwYZBH</recordid><startdate>201708</startdate><enddate>201708</enddate><creator>Tsukamoto, Hiroki</creator><creator>Yamagata, Yuki</creator><creator>Ukai, Ippo</creator><creator>Takeuchi, Shino</creator><creator>Okubo, Misaki</creator><creator>Kobayashi, Yohei</creator><creator>Kozakai, Sao</creator><creator>Kubota, Kanae</creator><creator>Mumasaki, Muneo</creator><creator>Kanemitsu, Yoshitomi</creator><creator>Matsumoto, Yotaro</creator><creator>Tomioka, Yoshihisa</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201708</creationdate><title>An inhibitory epitope of human Toll‐like receptor 4 resides on leucine‐rich repeat 13 and is recognized by a monoclonal antibody</title><author>Tsukamoto, Hiroki ; Yamagata, Yuki ; Ukai, Ippo ; Takeuchi, Shino ; Okubo, Misaki ; Kobayashi, Yohei ; Kozakai, Sao ; Kubota, Kanae ; Mumasaki, Muneo ; Kanemitsu, Yoshitomi ; Matsumoto, Yotaro ; Tomioka, Yoshihisa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4518-58340678c53c49021d392e42b238866e91afd97d5fddd4e8f9e4b68853ad670d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Amino Acid Motifs</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Cell Line</topic><topic>epitope</topic><topic>Epitopes - immunology</topic><topic>Humans</topic><topic>inhibitory monoclonal antibody</topic><topic>leucine‐rich repeat</topic><topic>lipopolysaccharide</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>MD‐2</topic><topic>Mice</topic><topic>Protein Multimerization</topic><topic>Protein Structure, Quaternary</topic><topic>Toll-Like Receptor 4 - chemistry</topic><topic>Toll-Like Receptor 4 - immunology</topic><topic>Toll-Like Receptor 4 - metabolism</topic><topic>Toll‐like receptor 4</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tsukamoto, Hiroki</creatorcontrib><creatorcontrib>Yamagata, Yuki</creatorcontrib><creatorcontrib>Ukai, Ippo</creatorcontrib><creatorcontrib>Takeuchi, Shino</creatorcontrib><creatorcontrib>Okubo, Misaki</creatorcontrib><creatorcontrib>Kobayashi, Yohei</creatorcontrib><creatorcontrib>Kozakai, Sao</creatorcontrib><creatorcontrib>Kubota, Kanae</creatorcontrib><creatorcontrib>Mumasaki, Muneo</creatorcontrib><creatorcontrib>Kanemitsu, Yoshitomi</creatorcontrib><creatorcontrib>Matsumoto, Yotaro</creatorcontrib><creatorcontrib>Tomioka, Yoshihisa</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>FEBS letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tsukamoto, Hiroki</au><au>Yamagata, Yuki</au><au>Ukai, Ippo</au><au>Takeuchi, Shino</au><au>Okubo, Misaki</au><au>Kobayashi, Yohei</au><au>Kozakai, Sao</au><au>Kubota, Kanae</au><au>Mumasaki, Muneo</au><au>Kanemitsu, Yoshitomi</au><au>Matsumoto, Yotaro</au><au>Tomioka, Yoshihisa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An inhibitory epitope of human Toll‐like receptor 4 resides on leucine‐rich repeat 13 and is recognized by a monoclonal antibody</atitle><jtitle>FEBS letters</jtitle><addtitle>FEBS Lett</addtitle><date>2017-08</date><risdate>2017</risdate><volume>591</volume><issue>16</issue><spage>2406</spage><epage>2416</epage><pages>2406-2416</pages><issn>0014-5793</issn><eissn>1873-3468</eissn><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.</abstract><cop>England</cop><pmid>28741733</pmid><doi>10.1002/1873-3468.12768</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Free Content; Alma/SFX Local Collection |
| subjects | Amino Acid Motifs Amino Acid Sequence Animals Antibodies, Monoclonal - immunology Cell Line epitope Epitopes - immunology Humans inhibitory monoclonal antibody leucine‐rich repeat lipopolysaccharide Lipopolysaccharides - pharmacology MD‐2 Mice Protein Multimerization Protein Structure, Quaternary Toll-Like Receptor 4 - chemistry Toll-Like Receptor 4 - immunology Toll-Like Receptor 4 - metabolism Toll‐like receptor 4 |
| title | 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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