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ID 51464
FullText URL
Author
Fushimi, Soichiro
Nakashima, Yuki
Itakura, Jyunya
Liu, Qiuying
Win, Min Min
Sun, Cuiming
Chen, Cao
Sato, Miwa
Mino, Megumi
Ogino, Tetsuya
Makino, Hirofumi
Yoshimura, Akihiko
Matsukawa, Akihiro Kakenhi
Abstract
MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4(+) T, CD8(+) T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFN gamma, naive Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFN gamma and decreased numbers of not only NK cells but also CD4(+) T and CD8(+) T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells.
Keywords
Acetaminophen
Hepatotoxicity
Liver immunology
Signaling pathway
Toxicology
Published Date
2012-09
Publication Title
Clinical Immunology
Volume
volume144
Issue
issue3
Publisher
Academic Press Inc Elsevier Science
Start Page
272
End Page
282
ISSN
1521-6616
Content Type
Journal Article
Official Url
http://dx.doi.org/10.1016/j.clim.2012.07.002
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/51459
language
英語
Copyright Holders
(C) 2012 Elsevier Inc. All rights reserved.
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author
Refereed
True
DOI
Web of Sience KeyUT