title: SOCS3 in T and NKT cells negatively regulates cytokine production and ameliorates ConA-induced hepatitis.
abstract: Suppressor of cytokine signaling 3 (SOCS3), a negative-feedback molecule for cytokine signaling, has been implicated in protection against liver injury. Previous studies have shown that overexpression of SOCS3 in the liver by adenovirus or membrane permeable recombinant protein protected the liver from various injuries. However it remained uncertain in which type of cells SOCS3 suppresses liver injury. In this study, we demonstrated that forced expression of SOCS3 in T and NKT cells suppressed ConA-induced hepatitis using T and NKT cell-specific SOCS3 transgenic (Lck-SOCS3 Tg) mice. IFN-gamma and IL-4 production was reduced in Lck-SOCS3 Tg mice as well as splenocytes treated with ConA. IFN-gamma and IL-4 levels were also reduced in Lck-SOCS3 Tg mice administrated with alpha-galactosylceramide, suggesting that SOCS3 in NKT cells has suppressive function. Sustained expression of SOCS3 in an NKT cell line also resulted in reduced expression of various cytokines and transcription factors. In contrast, T and NKT cell-specific SOCS3 conditional knockout (Lck-SOCS3 cKO) mice were hypersensitive to ConA-mediated hepatitis. Isolated SOCS3-deficient NKT cells produced higher levels of IFN-gamma and IL-4. These data indicate that SOCS3 plays a negative regulatory role in NKT cell activation and that forced expression of SOCS3 in NKT cells is effective in preventing hepatitis.
authors.affiliation: Department of Biomolecular Sciences, Saga University, 5-1-1 Nabeshima, Saga, Japan.
authors.forename: Mako
authors.initials: M
authors.lastname: Nakaya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Nakagawa
authors.forename: Yu
authors.initials: Y
authors.lastname: Wakabayashi
authors.forename: Takuma
authors.initials: T
authors.lastname: Ishizaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Kyoko
authors.initials: K
authors.lastname: Komai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006505:Hepatitis / Q000209:etiology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008934:Mitogens / Q000633:toxicity; D055611:Natural Killer T-Cells / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016207:Cytokines; D008934:Mitogens; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D003208:Concanavalin A