title: The NF-kappaB, p38 MAPK and STAT1 pathways differentially regulate the dsRNA-mediated innate immune responses of epidermal keratinocytes.
abstract: The epidermis is the primary boundary between the body and the environment, and it serves as the first line of defense against microbial pathogens. Production of chemokines and cytokines is an important step in the initiation of innate immune responses to viral infections. Epidermal keratinocytes produce IFN-alpha, -beta and macrophage inflammatory protein (MIP)-1alpha in response to double-stranded RNA (dsRNA) or viral infections. We showed that human keratinocytes produced cytokines [tumor necrosis factor (TNF)-alpha, IL-1beta and IL-15] and chemokines [MIP-1beta, RANTES and liver and activation-regulated chemokine (LARC)] in response to dsRNA, with activation of the nuclear factor kappaB (NF-kappaB), p38 mitogen-activated protein kinase (MAPK) and signal transducers and activators of transcription 1 (STAT1) pathways. To study the roles of these pathways in their production, we transfected keratinocytes with adenoviral vectors (Ax) carrying a dominant-negative form of inhibitor kappaB alpha (IkappaBalpha) (IkappaBalphaM), a dominant-negative mutant form of STAT1 (STAT1F) or suppressors of cytokine signaling 1 (SOCS1). Transfection with AxIkappaBalphaM or addition of a p38 inhibitor (SB203580) significantly decreased the dsRNA-mediated production of TNF-alpha, IL-1beta and MIP-1alpha, but not of IFN-beta, IL-15, MIP-1beta, RANTES or LARC. Transfection with AxSTAT1F or AxSOCS1 inhibited the dsRNA-mediated production of TNF-alpha, IL-15, MIP-1alpha, MIP-1beta, RANTES and LARC, but not IFN-beta or IL-1beta. In conclusion, the NF-kappaB, p38 MAPK and STAT1 pathways differentially regulate dsRNA-mediated innate immune responses in epidermal keratinocytes.
authors.affiliation: Department of Dermatology, Ehime University Graduate School of Medicine, Toon-city, Ehime 791-0295, Japan.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Dai
authors.forename: Koji
authors.initials: K
authors.lastname: Sayama
authors.forename: Mikiko
authors.initials: M
authors.lastname: Tohyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.forename: Lujun
authors.initials: L
authors.lastname: Yang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
authors.forename: Sho
authors.initials: S
authors.lastname: Tokumaru
authors.forename: Koji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D015603:Keratinocytes / Q000276:immunology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007093:Imidazoles; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011725:Pyridines; D012330:RNA, Double-Stranded; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000072000:NF-KappaB Inhibitor alpha; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580