title: CD4+ T-cell dysfunctions through the impaired lipid rafts ameliorate concanavalin A-induced hepatitis in sphingomyelin synthase 1-knockout mice.
abstract: Membrane microdomains consisting of sphingomyelin (SM) and cholesterol appear to be important for signal transduction in T-cell activation. The present study was designed to elucidate the role of membrane SM in vivo and in vitro using sphingomyelin synthase 1 (SMS1) knock out (SMS1(-/-)) mice and Concanavalin A (ConA)-induced hepatitis. After establishing SMS1(-/-) mice, we investigated CD4+ T-cell functions including proliferation, cytokine production and signal transduction in vivo. We also examined severity of hepatitis, cytokine production in serum and liver after ConA injection at a dose of 20 mg kg(-1). CD4+ T cells from SMS1(-/-) mice showed severe deficiency of membrane SM and several profound defects compared with wild-type controls as follows: (i) cellular proliferation and production of IL-2 and IFN-γ by co-cross-linking of CD3 and CD4; (ii) tyrosine phosphorylation of LAT and its association with ZAP-70; (iii) clustering and co-localization of TCR with lipid rafts. Consistent with these impaired CD4+ T-cell functions in vitro, SMS1(-/-) mice showed decreased serum levels of IL-6 and IFN-γ by ConA injection, which renders SMS1(-/-) mice less sensitive to ConA-induced hepatitis. These results indicated that the deficiency of membrane SM caused the CD4+ T-cell dysfunction through impaired lipid raft function contributed to protection of ConA-induced liver injury, suggesting that the membrane SM is critical for full T-cell activation both in vitro and in vivo.
authors.affiliation: Department of Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Lingli
authors.initials: L
authors.lastname: Dong
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.forename: Mari
authors.initials: M
authors.lastname: Itoh
authors.forename: Cheng-Ri
authors.initials: CR
authors.lastname: Huan
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Tong
authors.forename: Takuji
authors.initials: T
authors.lastname: Nakamura
authors.forename: Miyuki
authors.initials: M
authors.lastname: Miki
authors.forename: Haruka
authors.initials: H
authors.lastname: Iwao
authors.forename: Akio
authors.initials: A
authors.lastname: Nakajima
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sakai
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kawanami
authors.forename: Toshioki
authors.initials: T
authors.lastname: Sawaki
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Masaki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fukushima
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Fujita
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
authors.forename: Masato
authors.initials: M
authors.lastname: Yano
authors.forename: Toshiro
authors.initials: T
authors.lastname: Okazaki
authors.forename: Hisanori
authors.initials: H
authors.lastname: Umehara
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D003208:Concanavalin A / Q000276:immunology*; D006505:Hepatitis / Q000276:immunology*; D021962:Membrane Microdomains / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017855:Transferases (Other Substituted Phosphate Groups) / Q000172:deficiency* / Q000276:immunology
chemical_list: D003208:Concanavalin A; C556686:Sgms1 protein, mouse; D017855:Transferases (Other Substituted Phosphate Groups)