title: ΔNp63 regulates IL-33 and IL-31 signaling in atopic dermatitis.
abstract: Atopic dermatitis (AD) is the most common inflammatory skin disease with no well-delineated cause or effective cure. Here we show that the p53 family member p63, specifically the ΔNp63, isoform has a key role in driving keratinocyte activation in AD. We find that overexpression of ΔNp63 in transgenic mouse epidermis results in a severe skin phenotype that shares many of the key clinical, histological and molecular features associated with human AD. This includes pruritus, epidermal hyperplasia, aberrant keratinocyte differentiation, enhanced expression of selected cytokines and chemokines and the infiltration of large numbers of inflammatory cells including type 2  T-helper cells - features that are highly representative of AD dermatopathology. We further demonstrate several of these mediators to be direct transcriptional targets of ΔNp63 in keratinocytes. Of particular significance are two p63 target genes, IL-31 and IL-33, both of which are key players in the signaling pathways implicated in AD. Importantly, we find these observations to be in good agreement with elevated levels of ΔNp63 in skin lesions of human patients with AD. Our studies reveal an important role for ΔNp63 in the pathogenesis of AD and offer new insights into its etiology and possible therapeutic targets.
authors.affiliation: Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, USA.|Department of Internal Medicine, Catholic Health Systems, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Rizzo
authors.affiliation: Department of Oral Biology, State University of New York at Buffalo, School of Dental Medicine, Buffalo, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Oyelakin
authors.affiliation: Department of Oral Biology, State University of New York at Buffalo, School of Dental Medicine, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Min
authors.affiliation: Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Smalley
authors.affiliation: Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bard
authors.affiliation: Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nyquist
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Guttman-Yassky
authors.affiliation: Department of Dermatology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Dermatology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: De Benedetto
authors.affiliation: Department of Dermatology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Beck
authors.affiliation: Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Oral Biology, State University of New York at Buffalo, School of Dental Medicine, Buffalo, NY, USA.
authors.forename: R-A
authors.initials: RA
authors.lastname: Romano
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D000067596:Interleukin-33 / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D053677:Receptors, Oncostatin M / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; C488159:Il31ra protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D010750:Phosphoproteins; D018123:Receptors, Interleukin; D053677:Receptors, Oncostatin M; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C502588:interleukin-31, mouse; D007073:Immunoglobulin E