title: Interleukin-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions.
abstract: BACKGROUND
  Keloid scarring is a dermal fibroproliferative disorder characterized by increased fibroblast proliferation and excessive production of collagen and extracellular matrix (ECM) components. To date, the role of cytokines in keloid pathogenesis has not been completely unravelled. Interleukin (IL)-18 is a pro-inflammatory cytokine that plays important roles in wound healing, fibrogenesis and carcinogenesis.
  
  
  OBJECTIVE
  Our aim was to study the role of the IL-18 system in keloid pathogenesis.
  
  
  METHODS
  Expression and localization of IL-18 and its receptor (IL-18R) were investigated in normal skin and keloid tissues using Western blot and immunohistochemistry. We further studied the expression of the IL-18 system in normal and keloid-derived cell lines in a coculture model.
  
  
  RESULTS
  Results from Western blot and immunohistochemistry revealed that IL-18, IL-18Rα and IL-18Rβ expression was elevated in keloid tissue compared with normal skin tissue. Studies on the expression of IL-18 and its antagonist, IL-18 binding protein (IL-18BP), using a coculture model demonstrated severe IL-18/IL-18BP imbalance in keloid keratinocyte/keloid fibroblast (KK/KF) cocultures with significant elevation of bioactive IL-18 whereas IL-18BP levels remained the same. This overproduction of bioactive IL-18 in keloid cocultures could be due to increased caspase-1 and decreased caspase-3 expression in keloid tissue, as well as decreased soluble IL-10 levels observed in keloid cocultures. The important inductive effects of IL-18 on KFs were further underscored by the observation that exposure of KF to IL-18 resulted in increased collagen and ECM component synthesis, and increased secretion of profibrotic cytokines such as IL-6 and IL-8. Finally, the addition of phosphatidylinositol 3-kinase (PI3K), mitogen activation protein kinase (MAPK), specificity protein 1 (Sp1) and mammalian target of rapamycin (mTOR) inhibitors inhibited IL-18 secretion in keloid cocultures.
  
  
  CONCLUSIONS
  The present study has proven that the IL-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions. It also suggests a therapeutic potential of PI3K, MAPK, Sp1 and mTOR inhibitors in the treatment of keloid scarring.
authors: Department of Surgery, Centre for Craniofacial and Regenerative Biology, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.
authors: D V
authors: DV
authors: Do
authors: C T
authors: CT
authors: Ong
authors: Y T
authors: YT
authors: Khoo
authors: A
authors: A
authors: Carbone
authors: C P
authors: CP
authors: Lim
authors: S
authors: S
authors: Wang
authors: A
authors: A
authors: Mukhopadhyay
authors: X
authors: X
authors: Cao
authors: D H
authors: DH
authors: Cho
authors: X Q
authors: XQ
authors: Wei
authors: G
authors: G
authors: Bellone
authors: I
authors: I
authors: Lim
authors: T T
authors: TT
authors: Phan
mesh_terms: D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007627:Keloid / Q000209:etiology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020170:Caspase 1; D053148:Caspase 3; D003094:Collagen; D004791:Enzyme Inhibitors; D020382:Interleukin-18; D015850:Interleukin-6; D016209:Interleukin-8; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D053724:Receptors, Interleukin-18; D016329:Sp1 Transcription Factor; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human