title: Etanercept suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of interleukin (IL)-19, IL-20 and IL-24.
abstract: BACKGROUND
  Psoriasis is a Th17/Th1-mediated skin disease that often responds to antitumour necrosis factor (TNF)-α therapies, such as etanercept.
  
  
  OBJECTIVE
  To better define mechanisms by which etanercept improves psoriasis and to gain insight into disease pathogenesis.
  
  
  METHODS
  We investigated the early biochemical and cellular effects of etanercept on skin lesions in responder patients prior to substantial clinical improvement (≤ 4 weeks).
  
  
  RESULTS
  By 1 week, etanercept acutely suppressed gene expression of the interleukin (IL)-20 subfamily of cytokines (IL-19, IL-20, IL-24), which were found to be predominantly epidermis-derived and which are implicated in stimulating epidermal hyperplasia. Additionally, by 1 week of therapy, suppression of other keratinocyte-derived products (chemokines, antimicrobial proteins) occurred, while suppression of epidermal regenerative hyperplasia occurred within 1-3 weeks. Th17 elements (IL-23p19, IL-12p40, IL-17A, IL-22) were suppressed by 3-4 weeks. In vitro, TNF-α and IL-17A coordinately stimulated the expression of the IL-20 subfamily in normal keratinocytes.
  
  
  CONCLUSIONS
  Based on the rapid suppression of regenerative hyperplasia, chemokines and other keratinocyte-derived products, including the IL-20 subfamily, we propose that epidermal activation is a very early target of etanercept. As many of these keratinocyte markers are stimulated by TNF-α, their rapid downregulation is likely to reflect etanercept's antagonism of TNF-α. Additionally, decreased epidermal hyperplasia might result specifically from acute suppression of the IL-20 subfamily, which is also a likely consequence of etanercept's antagonism of TNF-α. Thus, the IL-20 subfamily has potential importance in the pathogenesis of psoriasis and therapeutic response to etanercept.
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA. frawang@med.umich.edu
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Smith
authors.forename: L
authors.initials: L
authors.lastname: Maier
authors.forename: W
authors.initials: W
authors.lastname: Xia
authors.forename: C
authors.initials: C
authors.lastname: Hammerberg
authors.forename: H
authors.initials: H
authors.lastname: Chubb
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Riblett
authors.forename: A
authors.initials: A
authors.lastname: Johnston
authors.forename: J E
authors.initials: JE
authors.lastname: Gudjonsson
authors.forename: Y
authors.initials: Y
authors.lastname: Helfrich
authors.forename: S
authors.initials: S
authors.lastname: Kang
authors.forename: G J
authors.initials: GJ
authors.lastname: Fisher
authors.forename: J J
authors.initials: JJ
authors.lastname: Voorhees
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000502:physiology; D015536:Down-Regulation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D000068800:Etanercept; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000502:physiology; D008213:Lymphocyte Activation / Q000502:physiology; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D012038:Regeneration / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D007378:Interleukins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept