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

Research output: Contribution to journalArticle

8 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 languageEnglish
Pages (from-to)272-282
Number of pages11
JournalClinical Immunology
Volume144
Issue number3
DOIs
Publication statusPublished - 2012 Sep 1

Keywords

  • Acetaminophen
  • Hepatotoxicity
  • Liver immunology
  • Signaling pathway
  • Toxicology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Wakabayashi, H., Ito, T., Fushimi, S., Nakashima, Y., Itakura, J., Qiuying, L., Win, M. M., Cuiming, S., Chen, C., Sato, M., Mino, M., Ogino, T., Makino, H., Yoshimura, A., & Matsukawa, A. (2012). Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice. Clinical Immunology, 144(3), 272-282. https://doi.org/10.1016/j.clim.2012.07.002