title: Human β-defensin-3 increases the expression of interleukin-37 through CCR6 in human keratinocytes.
abstract: BACKGROUND
  Interleukin (IL)-37, a new member of the IL-1 family, is characterized as a fundamental inhibitor of innate immunity: it dampens the production of proinflammatory cytokines, protects against inflammatory and autoimmune diseases, and plays a potent immunosuppressive role in the pathogenesis of psoriasis. IL-37 is highly expressed in psoriatic skin, in which human β-defensins (hBDs) have been detected. Although hBDs enhance the production of cytokines, including IL-1 cytokines, whether they stimulate the production of IL-37 remains unclear.
  
  
  OBJECTIVE
  To assess the ability of hBDs to stimulate IL-37 expression/production by human keratinocytes and to determine the mechanism involved.
  
  
  METHODS
  Real-time PCR and Western blotting were used to evaluate IL-37 expression. Caspase activities were assessed using colorimetric assay kits. A CCR6 antibody, siRNA, and caspase, Smad3, MAPK and NF-κB inhibitors were used to investigate the signaling mechanism of hBDs.
  
  
  RESULTS
  Among the four hBDs used, only hBD-3 up-regulated the mRNA and protein expression of IL-37. The combination of TNF-α, EGF and poly (I:C) with hBD-3 synergistically enhanced the mRNA but not the protein expression of IL-37. Furthermore, hBD-3 increased the release of IL-37 into the culture supernatants. Evaluation of the signaling mechanism of hBD-3 suggested that caspases 1 and 4, Smad3, CCR6, MAPKs and NF-κB were required for hBD-3-mediated IL-37 expression.
  
  
  CONCLUSIONS
  The finding that hBD-3 stimulates IL-37 expression, a novel target for the pathogenesis and therapy of cutaneous inflammatory diseases, provides evidence that hBDs contribute to the suppression of inflammatory and innate immune responses through the regulation of IL-37 expression.
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Rithee
authors.initials: R
authors.lastname: Smithrithee
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address: francois@juntendo.ac.jp.
authors.forename: François
authors.initials: F
authors.lastname: Niyonsaba
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Chanisa
authors.initials: C
authors.lastname: Kiatsurayanon
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ushio
authors.affiliation: Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shigaku
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology; D020170:Caspase 1 / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011565:Psoriasis / Q000276:immunology; D034741:RNA, Small Interfering / Q000378:metabolism; D054399:Receptors, CCR6 / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D023083:beta-Defensins / Q000378:metabolism*
chemical_list: C106311:CCR6 protein, human; C422950:DEFB103A protein, human; C508587:IL37 protein, human; D007375:Interleukin-1; D016328:NF-kappa B; D034741:RNA, Small Interfering; D054399:Receptors, CCR6; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D023083:beta-Defensins; C093516:CASP4 protein, human; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: CCR6; Caspase; Human β-defensin; Interleukin-37; Keratinocyte