title: NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells.
abstract: Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius-Maximilians-University, Würzburg D-97080, Germany.|Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg D-97080, Germany.|Faculty of Medicine, Department of Medical Biochemistry, Liver Laboratory, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Hani
authors.initials: H
authors.lastname: Alrefai
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius-Maximilians-University, Würzburg D-97080, Germany.
authors.forename: Khalid
authors.initials: K
authors.lastname: Muhammad
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius-Maximilians-University, Würzburg D-97080, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Rudolf
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius-Maximilians-University, Würzburg D-97080, Germany.
authors.forename: Duong Anh Thuy
authors.initials: DA
authors.lastname: Pham
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius-Maximilians-University, Würzburg D-97080, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Klein-Hessling
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius-Maximilians-University, Würzburg D-97080, Germany.
authors.forename: Amiya K
authors.initials: AK
authors.lastname: Patra
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius-Maximilians-University, Würzburg D-97080, Germany.
authors.forename: Andris
authors.initials: A
authors.lastname: Avots
authors.affiliation: TRON gGmbH-Translational Oncology, Johannes-Gutenberg-University Medical Center, Mainz D-55131, Germany.
authors.forename: Valesca
authors.initials: V
authors.lastname: Bukur
authors.affiliation: TRON gGmbH-Translational Oncology, Johannes-Gutenberg-University Medical Center, Mainz D-55131, Germany.|Johannes-Gutenberg-University Medical Center gGmbH, Mainz D-55131, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.affiliation: Institute for Immunology, University Medical Center, Johannes-Gutenberg-University, Mainz D-55131, Germany.
authors.forename: Stefan
authors.identifier: 0000-0003-3034-0017
authors.initials: S
authors.lastname: Tenzer
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg D-97080, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebeler
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg D-97080, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kerstan
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius-Maximilians-University, Würzburg D-97080, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Serfling
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D000077271:Imiquimod; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011565:Psoriasis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000634:Aminoquinolines; C556062:IL10 protein, mouse; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016753:Interleukin-10; D000077271:Imiquimod