Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

Hiroshi Wakabayashi; Toshihiro Ito; Soichiro Fushimi; Yuki Nakashima; Jyunya Itakura; Liu Qiuying; Min Min Win; Sun Cuiming; Cao Chen; Miwa Sato; Megumi Mino; Tetsuya Ogino; Hirofumi Makino; Akihiko Yoshimura; Akihiro Matsukawa

doi:10.1016/j.clim.2012.07.002

Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

Hiroshi Wakabayashi, Toshihiro Ito, Soichiro Fushimi, Yuki Nakashima, Jyunya Itakura, Liu Qiuying, Min Min Win, Sun Cuiming, Cao Chen, Miwa Sato, Megumi Mino, Tetsuya Ogino, Hirofumi Makino, Akihiko Yoshimura, Akihiro Matsukawa

Department of Microbiology and Immunology

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

11 Citations (Scopus)

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 IFNγ, naïve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ 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.

Original language	English
Pages (from-to)	272-282
Number of pages	11
Journal	Clinical Immunology
Volume	144
Issue number	3
DOIs	https://doi.org/10.1016/j.clim.2012.07.002
Publication status	Published - 2012 Sept

Keywords

Acetaminophen
Hepatotoxicity
Liver immunology
Signaling pathway
Toxicology

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.clim.2012.07.002

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@article{896530c24fc046dc92d74d7527136f5f,

title = "Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice",

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 IFNγ, na{\"i}ve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ 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",

author = "Hiroshi Wakabayashi and Toshihiro Ito and Soichiro Fushimi and Yuki Nakashima and Jyunya Itakura and Liu Qiuying and Win, {Min Min} and Sun Cuiming and Cao Chen and Miwa Sato and Megumi Mino and Tetsuya Ogino and Hirofumi Makino and Akihiko Yoshimura and Akihiro Matsukawa",

note = "Funding Information: We thank Mr. Hiroyuki Watanabe and Mr. Yasuharu Arashima for their excellent technical assistance. This work was supported in part by grants from The Ministry of Education, Science, Sports and Culture , and The Ministry of Health and Welfare , Japan.",

year = "2012",

month = sep,

doi = "10.1016/j.clim.2012.07.002",

language = "English",

volume = "144",

pages = "272--282",

journal = "Clinical Immunology",

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T1 - Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

AU - Wakabayashi, Hiroshi

AU - Ito, Toshihiro

AU - Fushimi, Soichiro

AU - Nakashima, Yuki

AU - Itakura, Jyunya

AU - Qiuying, Liu

AU - Win, Min Min

AU - Cuiming, Sun

AU - Chen, Cao

AU - Sato, Miwa

AU - Mino, Megumi

AU - Ogino, Tetsuya

AU - Makino, Hirofumi

AU - Yoshimura, Akihiko

AU - Matsukawa, Akihiro

N1 - Funding Information: We thank Mr. Hiroyuki Watanabe and Mr. Yasuharu Arashima for their excellent technical assistance. This work was supported in part by grants from The Ministry of Education, Science, Sports and Culture , and The Ministry of Health and Welfare , Japan.

PY - 2012/9

Y1 - 2012/9

N2 - 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 IFNγ, naïve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ 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.

AB - 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 IFNγ, naïve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ 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.

KW - Acetaminophen

KW - Hepatotoxicity

KW - Liver immunology

KW - Signaling pathway

KW - Toxicology

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JF - Clinical Immunology

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ER -

Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

Abstract

Keywords

ASJC Scopus subject areas

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