Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages.
While Wiskott-Aldrich syndrome protein (WASP) plays critical roles in TCR signaling as an adaptor molecule, how it transduces innate immune signals remains to be elucidated. To investigate the roles of WASP in innate immune cells, we established bone marrow-derived macrophage (BMDM) cell lines from...
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2012-01-01
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doaj-2deba24bb6884608bfde6e6485764c882020-11-24T22:08:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0171e3035110.1371/journal.pone.0030351Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages.Chisato SakumaMitsuru SatoTakato TakenouchiJoe ChibaHiroshi KitaniWhile Wiskott-Aldrich syndrome protein (WASP) plays critical roles in TCR signaling as an adaptor molecule, how it transduces innate immune signals remains to be elucidated. To investigate the roles of WASP in innate immune cells, we established bone marrow-derived macrophage (BMDM) cell lines from WASP15 transgenic (Tg) mice overexpressing the WASP N-terminal region (exons 1-5). Upon LPS stimulation, WASP15 Tg BMDM cell lines produce lower levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-12p40 than the wild-type BMDM cell line. In addition, the production of nitric oxide by WASP15 Tg BMDM cells in response to LPS and IFN-γ was significantly impaired. Furthermore, we uncovered that the WASP N-terminal domain associates with the Src homology (SH) 3 domain of Bruton's tyrosine kinase (Btk). Overexpression of the WASP N-terminal domain diminishes the extent of tyrosine phosphorylation of endogenous WASP in WASP15 Tg BMDM cells, possibly by interfering with the specific binding between endogenous WASP and Btk during LPS signaling. These observations strongly suggest that the interaction between WASP N-terminal domain and Btk plays important roles in the LPS signaling cascade in innate immunity.http://europepmc.org/articles/PMC3257260?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chisato Sakuma Mitsuru Sato Takato Takenouchi Joe Chiba Hiroshi Kitani |
spellingShingle |
Chisato Sakuma Mitsuru Sato Takato Takenouchi Joe Chiba Hiroshi Kitani Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages. PLoS ONE |
author_facet |
Chisato Sakuma Mitsuru Sato Takato Takenouchi Joe Chiba Hiroshi Kitani |
author_sort |
Chisato Sakuma |
title |
Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages. |
title_short |
Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages. |
title_full |
Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages. |
title_fullStr |
Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages. |
title_full_unstemmed |
Critical roles of the WASP N-terminal domain and Btk in LPS-induced inflammatory response in macrophages. |
title_sort |
critical roles of the wasp n-terminal domain and btk in lps-induced inflammatory response in macrophages. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
While Wiskott-Aldrich syndrome protein (WASP) plays critical roles in TCR signaling as an adaptor molecule, how it transduces innate immune signals remains to be elucidated. To investigate the roles of WASP in innate immune cells, we established bone marrow-derived macrophage (BMDM) cell lines from WASP15 transgenic (Tg) mice overexpressing the WASP N-terminal region (exons 1-5). Upon LPS stimulation, WASP15 Tg BMDM cell lines produce lower levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-12p40 than the wild-type BMDM cell line. In addition, the production of nitric oxide by WASP15 Tg BMDM cells in response to LPS and IFN-γ was significantly impaired. Furthermore, we uncovered that the WASP N-terminal domain associates with the Src homology (SH) 3 domain of Bruton's tyrosine kinase (Btk). Overexpression of the WASP N-terminal domain diminishes the extent of tyrosine phosphorylation of endogenous WASP in WASP15 Tg BMDM cells, possibly by interfering with the specific binding between endogenous WASP and Btk during LPS signaling. These observations strongly suggest that the interaction between WASP N-terminal domain and Btk plays important roles in the LPS signaling cascade in innate immunity. |
url |
http://europepmc.org/articles/PMC3257260?pdf=render |
work_keys_str_mv |
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