title: Expression of IL-33 in the epidermis: The mechanism of induction by IL-17.
abstract: BACKGROUND
  Interleukin (IL)-33 is a dual functional, IL-1 family member cytokine, whose exact roles in inflammatory skin diseases are still unknown. IL-17A is a key cytokine in the pathogenesis of psoriasis.
  
  
  OBJECTIVE
  We investigated if IL-17A could induce IL-33 in epidermal keratinocytes, and the signaling mechanisms involved.
  
  
  METHODS
  IL-33 levels were evaluated by RT-PCR and western blot in human keratinocytes following IL-17A simulation. IL-33 immunohistochemical staining of psoriatic skin samples was also performed and compared with that of control tissues. The role of signaling pathways downstream of IL-17A was investigated using small molecule inhibitors of EGFR, ERK, p38, and JAK. Adenovirus vector expressing dominant negative STAT1 was also utilized.
  
  
  RESULTS
  IL-33 and its receptor, ST2L, were expressed in the psoriatic epidermis, and the associated infiltrating cells. IL-17A induced IL-33 expression at mRNA and protein levels in a time- and concentration-dependent manner. IL-17A caused phosphorylation of EGFR, ERK, p38, and STAT1. IL-17A-induced IL-33 expression was blocked by the addition of EGFR, ERK, p38, and JAK inhibitors, and dominant negative STAT1-expressing adenovirus vector.
  
  
  CONCLUSIONS
  IL-17A induced IL-33 in NHEKs through EGFR, ERK, p38, and JAK/STAT1 pathways, which were necessary for the induction of IL-33. IL-33, induced by IL-17A in epidermal keratinocytes, may be involved in the pathophysiology of inflammatory skin diseases, including psoriasis.
authors.affiliation: Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Jitlada
authors.initials: J
authors.lastname: Meephansan
authors.forename: Mayumi
authors.initials: M
authors.lastname: Komine
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tsuda
authors.forename: Masaru
authors.initials: M
authors.lastname: Karakawa
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tominaga
authors.forename: Mamitaro
authors.initials: M
authors.lastname: Ohtsuki
mesh_terms: D016207:Cytokines / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D000072179:Interleukin-1 Receptor-Like 1 Protein; D020381:Interleukin-17 / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D011565:Psoriasis / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D020381:Interleukin-17; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: IL-17; IL-33; Normal human keratinocytes; Psoriasis; Signaling pathway