title: Overexpression of phospholipase Cε in keratinocytes upregulates cytokine expression and causes dermatitis with acanthosis and T-cell infiltration.
abstract: Phospholipase Cε (PLCε) is an effector of Ras and Rap small GTPases. We showed previously using PLCε-deficient mice that PLCε plays a critical role in activation of cytokine production in non-immune skin cells in a variety of inflammatory reactions. For further investigation of its role in inflammation, we created transgenic mice overexpressing PLCε in epidermal keratinocytes. The resulting transgenic mice spontaneously developed skin inflammation as characterized by formation of adherent silvery scales, excessive growth of keratinocytes, and aberrant infiltration of immune cells such as T cells and DC. Development of the skin symptoms correlated well with increased expression of factors implicated in human inflammatory skin diseases, such as IL-23, in keratinocytes, and with the accumulation of CD4(+) T cells producing IL-22, a potent inducer of keratinocyte proliferation. Intradermal injection of a blocking antibody against IL-23 as well as treatment with the immunosuppressant FK506 reversed these skin phenotypes, which was accompanied by suppression of the IL-22-producing T-cell infiltration. These results reveal a crucial role of PLCε in the development of skin inflammation and suggest a mechanism in which PLCε induces the production of cytokines including IL-23 from keratinocytes, leading to the activation of IL-22-producing T cells.
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takenaka
authors.forename: Hironori
authors.initials: H
authors.lastname: Edamatsu
authors.forename: Noboru
authors.initials: N
authors.lastname: Suzuki
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Saito
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inoue
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.forename: Lizhi
authors.initials: L
authors.lastname: Hu
authors.forename: Tohru
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D003872:Dermatitis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053759:Interleukin-23 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000276:immunology; D007378:Interleukins / Q000032:analysis / Q000276:immunology; D015603:Keratinocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054801:Phosphoinositide Phospholipase C / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology; D015854:Up-Regulation; D000097043:Interleukin-22
chemical_list: D019138:Antibodies, Blocking; D016207:Cytokines; D007166:Immunosuppressive Agents; D053759:Interleukin-23; D007378:Interleukins; D054801:Phosphoinositide Phospholipase C; D016559:Tacrolimus; D000097043:Interleukin-22; C423320:phospholipase C epsilon