title: SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes.
abstract: Toll-like receptor (TLR)3 is a receptor for virus-associated double-stranded RNA, and triggers antiviral immune responses during viral infection. Epidermal keratinocytes express TLR3 and provide an innate immune defense against viral infection. Since the intracellular regulatory mechanism is unknown, we hypothesized that the signal transducers and activators of transcription (STAT)-suppressors of cytokine signaling (SOCS) system regulates the innate immune response of keratinocytes. Treatment with polyinosinic-polycytidylic acid (poly(I:C)) resulted in the rapid translocation of IFN regulatory factor (IRF)-3 into the nucleus, followed by phosphorylation of STAT1 and STAT3. The activation of STATs by poly(I:C) probably occurs in an indirect fashion, through poly(I:C)-induced IFN. We infected cells with the dominant-negative forms of STAT1 (STAT1F), STAT3 (STAT3F), and SOCS1 using adenovirus vectors. Infection with STAT1F suppressed the induction of macrophage inflammatory protein (MIP)-1alpha by poly(I:C), whereas STAT3F had a minimal effect, which indicates that STAT1 mediates MIP-1alpha induction. SOCS1, which is a negative feedback regulator of STAT1 signaling, was induced by treatment with poly(I:C). SOCS1 infection inhibited the phosphorylation of STAT1 and significantly reduced poly(I:C)-induced MIP-1alpha production. Furthermore, STAT1-SOCS1 regulated poly(I:C)-induced TLR3 and IRF-7 expression. However, SOCS1 did not affect NF-kappaB signaling. Thus, the STAT1-SOCS1 pathway regulates the innate immune response via TLR3 signaling in epidermal keratinocytes.
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Toon-city, Ehime, Japan.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Dai
authors.forename: Koji
authors.initials: K
authors.lastname: Sayama
authors.forename: Kenshi
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Mikiko
authors.initials: M
authors.lastname: Tohyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hanakawa
authors.forename: Sho
authors.initials: S
authors.lastname: Tokumaru
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yahata
authors.forename: Lujun
authors.initials: L
authors.lastname: Yang
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Koji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D025461:Feedback, Physiological / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000032:analysis / Q000187:drug effects / Q000502:physiology; D050839:Interferon Regulatory Factor-7 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000737:chemistry / Q000276:immunology* / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000032:analysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000032:analysis / Q000502:physiology
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D047908:Intracellular Signaling Peptides and Proteins; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011070:Poly I-C