Cargando…
Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88
TLR4 polymorphisms such as Asp299Gly and Thr399Ile related to Gram-negative sepsis have been reported to result in significantly blunted responsiveness to LPS. Our study group previously screened other TLR4 polymorphic variants by checking the NF-κB activation in comparison to wild type (WT) TLR4 in...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504268/ https://www.ncbi.nlm.nih.gov/pubmed/32513051 http://dx.doi.org/10.1177/1753425920927479 |
_version_ | 1784581297875714048 |
---|---|
author | Yang, Yajie Hu, Yan Zhou, Yile Liang, Tao Tang, Haihong Ju, Huihui Shi, Qiqing Fang, Hao |
author_facet | Yang, Yajie Hu, Yan Zhou, Yile Liang, Tao Tang, Haihong Ju, Huihui Shi, Qiqing Fang, Hao |
author_sort | Yang, Yajie |
collection | PubMed |
description | TLR4 polymorphisms such as Asp299Gly and Thr399Ile related to Gram-negative sepsis have been reported to result in significantly blunted responsiveness to LPS. Our study group previously screened other TLR4 polymorphic variants by checking the NF-κB activation in comparison to wild type (WT) TLR4 in human embryonic kidney 293T cells. In this study, we found that the Lys694Arg (K694R) polymorphism reduced the activation of NF-κB, and the production of downstream inflammatory factors IL-1, TNF-α and IL-6, representing the K694R polymorphism, led to blunted responsiveness to LPS. Then, we examined the influence of the K694R polymorphism on total and cell-surface TLR4 expression by Western blotting and flow cytometry, respectively, but observed no differences between the K694R polymorphism and WT TLR4. We also used co-immunoprecipitation to determine the interaction of the K694R polymorphism and WT TLR4 with their co-receptor myeloid differentiation factor 2 (MD2) and their downstream signal adaptor MyD88. We found that K694R reduced the recruitment of MyD88 in TLR4 signalling but had no impact on the interaction with MD2. |
format | Online Article Text |
id | pubmed-8504268 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-85042682021-10-12 Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88 Yang, Yajie Hu, Yan Zhou, Yile Liang, Tao Tang, Haihong Ju, Huihui Shi, Qiqing Fang, Hao Innate Immun Original Articles TLR4 polymorphisms such as Asp299Gly and Thr399Ile related to Gram-negative sepsis have been reported to result in significantly blunted responsiveness to LPS. Our study group previously screened other TLR4 polymorphic variants by checking the NF-κB activation in comparison to wild type (WT) TLR4 in human embryonic kidney 293T cells. In this study, we found that the Lys694Arg (K694R) polymorphism reduced the activation of NF-κB, and the production of downstream inflammatory factors IL-1, TNF-α and IL-6, representing the K694R polymorphism, led to blunted responsiveness to LPS. Then, we examined the influence of the K694R polymorphism on total and cell-surface TLR4 expression by Western blotting and flow cytometry, respectively, but observed no differences between the K694R polymorphism and WT TLR4. We also used co-immunoprecipitation to determine the interaction of the K694R polymorphism and WT TLR4 with their co-receptor myeloid differentiation factor 2 (MD2) and their downstream signal adaptor MyD88. We found that K694R reduced the recruitment of MyD88 in TLR4 signalling but had no impact on the interaction with MD2. SAGE Publications 2020-06-08 2021-08 /pmc/articles/PMC8504268/ /pubmed/32513051 http://dx.doi.org/10.1177/1753425920927479 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by-nc/4.0/Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Original Articles Yang, Yajie Hu, Yan Zhou, Yile Liang, Tao Tang, Haihong Ju, Huihui Shi, Qiqing Fang, Hao Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88 |
title | Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88 |
title_full | Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88 |
title_fullStr | Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88 |
title_full_unstemmed | Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88 |
title_short | Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88 |
title_sort | lys694arg polymorphism leads to blunted responses to lps by interfering tlr4 with recruitment of myd88 |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504268/ https://www.ncbi.nlm.nih.gov/pubmed/32513051 http://dx.doi.org/10.1177/1753425920927479 |
work_keys_str_mv | AT yangyajie lys694argpolymorphismleadstobluntedresponsestolpsbyinterferingtlr4withrecruitmentofmyd88 AT huyan lys694argpolymorphismleadstobluntedresponsestolpsbyinterferingtlr4withrecruitmentofmyd88 AT zhouyile lys694argpolymorphismleadstobluntedresponsestolpsbyinterferingtlr4withrecruitmentofmyd88 AT liangtao lys694argpolymorphismleadstobluntedresponsestolpsbyinterferingtlr4withrecruitmentofmyd88 AT tanghaihong lys694argpolymorphismleadstobluntedresponsestolpsbyinterferingtlr4withrecruitmentofmyd88 AT juhuihui lys694argpolymorphismleadstobluntedresponsestolpsbyinterferingtlr4withrecruitmentofmyd88 AT shiqiqing lys694argpolymorphismleadstobluntedresponsestolpsbyinterferingtlr4withrecruitmentofmyd88 AT fanghao lys694argpolymorphismleadstobluntedresponsestolpsbyinterferingtlr4withrecruitmentofmyd88 |