PMID- 22050194
OWN - NLM
STAT- MEDLINE
DCOM- 20120830
LR  - 20211203
IS  - 1365-2133 (Electronic)
IS  - 0007-0963 (Linking)
VI  - 166
IP  - 6
DP  - 2012 Jun
TI  - Interleukin-18 system plays an important role in keloid pathogenesis via 
      epithelial-mesenchymal interactions.
PG  - 1275-88
LID - 10.1111/j.1365-2133.2011.10721.x [doi]
AB  - 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. OBJECTIVES: Our aim was to study the role of the 
      IL-18 system in keloid pathogenesis. MATERIALS AND 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-18Ralpha and IL-18Rbeta 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.
CI  - (c) 2012 The Authors. BJD (c) 2012 British Association of Dermatologists 2012.
FAU - Do, D V
AU  - Do DV
AD  - Department of Surgery, Centre for Craniofacial and Regenerative Biology, National 
      University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.
FAU - Ong, C T
AU  - Ong CT
FAU - Khoo, Y T
AU  - Khoo YT
FAU - Carbone, A
AU  - Carbone A
FAU - Lim, C P
AU  - Lim CP
FAU - Wang, S
AU  - Wang S
FAU - Mukhopadhyay, A
AU  - Mukhopadhyay A
FAU - Cao, X
AU  - Cao X
FAU - Cho, D H
AU  - Cho DH
FAU - Wei, X Q
AU  - Wei XQ
FAU - Bellone, G
AU  - Bellone G
FAU - Lim, I
AU  - Lim I
FAU - Phan, T T
AU  - Phan TT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120514
PL  - England
TA  - Br J Dermatol
JT  - The British journal of dermatology
JID - 0004041
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Interleukin-18)
RN  - 0 (Interleukin-6)
RN  - 0 (Interleukin-8)
RN  - 0 (Receptors, Interleukin-18)
RN  - 0 (Sp1 Transcription Factor)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Caspase 1/metabolism
MH  - Caspase 3/metabolism
MH  - Cells, Cultured
MH  - Collagen/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial-Mesenchymal Transition/*physiology
MH  - Fibroblasts/drug effects/metabolism
MH  - Humans
MH  - Interleukin-18/pharmacology/*physiology
MH  - Interleukin-6/metabolism
MH  - Interleukin-8/metabolism
MH  - Keloid/*etiology
MH  - Keratinocytes/drug effects/metabolism
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Receptors, Interleukin-18/metabolism
MH  - Sp1 Transcription Factor/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
EDAT- 2011/11/05 06:00
MHDA- 2012/08/31 06:00
CRDT- 2011/11/05 06:00
PHST- 2011/11/05 06:00 [entrez]
PHST- 2011/11/05 06:00 [pubmed]
PHST- 2012/08/31 06:00 [medline]
AID - 10.1111/j.1365-2133.2011.10721.x [doi]
PST - ppublish
SO  - Br J Dermatol. 2012 Jun;166(6):1275-88. doi: 10.1111/j.1365-2133.2011.10721.x. 
      Epub 2012 May 14.