title: Alteration of the EphA2/Ephrin-A signaling axis in psoriatic epidermis.
abstract: EphA2 is a receptor tyrosine kinase (RTK) that triggers keratinocyte differentiation upon activation and subsequent downregulation by ephrin-A1 ligand. The objective of this study was to determine whether the EphA2/ephrin-A1 signaling axis was altered in psoriasis, an inflammatory skin condition in which keratinocyte differentiation is abnormal. Microarray analysis of skin biopsies from psoriasis patients revealed increased mRNA transcripts for several members of this RTK family in plaques, including the EphA1, EphA2, and EphA4 subtypes prominently expressed by keratinocytes. Of these, EphA2 showed the greatest upregulation, a finding that was confirmed by quantitative reverse-transcriptase-PCR, immunohistochemistry (IHC), and ELISA. In contrast, psoriatic lesions exhibited reduced ephrin-A ligand immunoreactivity. Exposure of primary keratinocytes induced to differentiate in high calcium or a three-dimensional (3D) raft culture of human epidermis to a combination of growth factors and cytokines elevated in psoriasis increased EphA2 mRNA and protein expression while inducing S100A7 and disrupting differentiation. Pharmacological delivery of a soluble ephrin-A1 peptidomimetic ligand led to a reduction in EphA2 expression and ameliorated proliferation and differentiation in raft cultures exposed to EGF and IL-1α. These findings suggest that ephrin-A1-mediated downregulation of EphA2 supports keratinocyte differentiation in the context of cytokine perturbation.
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Gordon
authors.affiliation: Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Kochkodan
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Hanz
authors.initials: H
authors.lastname: Blatt
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Samantha Y
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Kaplan
authors.affiliation: Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnston
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hoover
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Bethanee J
authors.initials: BJ
authors.lastname: Schlosser
authors.affiliation: Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: s-getsios@northwestern.edu.
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
mesh_terms: D001706:Biopsy; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D036382:Ephrin-A1 / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011565:Psoriasis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D036104:Receptor, EphA2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016207:Cytokines; D036382:Ephrin-A1; D004815:Epidermal Growth Factor; D036104:Receptor, EphA2