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, 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.
authors.affiliation: Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.forename: Soichiro
authors.initials: S
authors.lastname: Fushimi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Jyunya
authors.initials: J
authors.lastname: Itakura
authors.forename: Liu
authors.initials: L
authors.lastname: Qiuying
authors.forename: Min Min
authors.initials: MM
authors.lastname: Win
authors.forename: Sun
authors.initials: S
authors.lastname: Cuiming
authors.forename: Cao
authors.initials: C
authors.lastname: Chen
authors.forename: Miwa
authors.initials: M
authors.lastname: Sato
authors.forename: Megumi
authors.initials: M
authors.lastname: Mino
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ogino
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsukawa
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000172:deficiency* / Q000378:metabolism*
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; D012097:Repressor Proteins; C433764:Spred2 protein, mouse; D000082:Acetaminophen; D007371:Interferon-gamma