title: Nuclear expression of IL-33 in epidermal keratinocytes promotes wound healing in mice.
abstract: BACKGROUND
  Skin is the outermost tissue of the human body, and works as a mechanical, chemical, and biological barrier. The epidermis is the uppermost layer of the skin, and keratinocytes constitute the majority of epidermal cells. Wounds are disruptions of skin integrity, and cause tremendous disadvantages to humans; accordingly, rapid wound healing is very important. Interleukin (IL)-33 is expressed in barrier tissue cells, such as epithelial and endothelial cells. Upon injury, IL-33 is released to stimulate immune cells, functioning as an "alarmin." ST2 is a receptor for IL-33; its soluble form (s)ST2 acts as a decoy receptor and competes for IL-33 binding.
  
  
  OBJECTIVE
  We aimed to clarify the role of IL-33 in wound healing.
  
  
  METHODS
  Wild-type (WT), IL-33 knockout (IL33 KO) mice, and sST2 transgenic (Tg) mice were wounded with a 4-mm punch, and the wound healing process was compared. Immunohistochemical analyses were performed to detect macrophages, neutrophils, and mast cells. Total RNA was extracted from the skin samples and real-time PCR was performed. An in vitro scratch wound assay was performed.
  
  
  RESULTS
  Wound healing was delayed in IL33 KO mice compared to WT mice, while wound healing in sST2 Tg mice was comparable to that of WT mice. A histological examination showed delayed elongation of the epidermal tongue in IL-33 KO mice. An immunohistochemical study revealed prolonged neutrophilic infiltration at a later stage in IL-33 KO mice. IL-6, IL-1β, and CXCL1 transcripts were more abundant in the wounds of IL-33 KO mice than WT mice. Intraperitoneal administration of an NFκB inhibitor to IL-33 KO mice normalized the delayed wound healing and the enhanced expression of IL-6 in IL-33 KO mice. Epidermal keratinocytes from IL-33 KO mice showed delayed wound closure compared to those from WT mice.
  
  
  CONCLUSIONS
  Our results indicate that nuclear IL-33, but not IL-33 as a cytokine, has beneficial effects on wound healing in mice, probably by suppressing NFκB to inhibit excessive inflammation and by maintaining keratinocyte proliferation or migration for epithelialization.
authors.affiliation: Departments of Dermatology at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: kiyumoto-oshio@hotmail.co.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Oshio
authors.affiliation: Departments of Dermatology at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Departments of Biochemistry at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: mkomine12@jichi.ac.jp.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Komine
authors.affiliation: Departments of Dermatology at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: thidet@jichi.ac.jp.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Departments of Biochemistry at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: shintomi@jichi.ac.jp.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Tominaga
authors.affiliation: Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Electronic address: saito-hr@ncchd.go.jp.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: snakae@ims.u-tokyo.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Departments of Dermatology at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: mamitaro@jichi.ac.jp.
authors.forename: Mamitaro
authors.initials: M
authors.lastname: Ohtsuki
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D061251:Primary Cell Culture; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014945:Wound Healing / Q000502:physiology*
chemical_list: C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33
keywords: Epithelialization; IL-33; Keratinocytes; Nuclear expression; Wound healing