Interleukin-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions

D. V. Do, C. T. Ong, Y. T. Khoo, A. Carbone, C. P. Lim, S. Wang, A. Mukhopadhyay, X. Cao, Dae Ho Cho, X. Q. Wei, G. Bellone, I. Lim, T. T. Phan

Research output: Contribution to journalArticle

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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. 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-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.

Original languageEnglish
Pages (from-to)1275-1288
Number of pages14
JournalBritish Journal of Dermatology
Volume166
Issue number6
DOIs
Publication statusPublished - 2012 Jun 1
Externally publishedYes

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Keloid
Interleukin-18
Coculture Techniques
Interleukins
Phosphatidylinositol 3-Kinase
Sirolimus
Cytokines
Mitogens
Protein Kinases
Skin
Cicatrix
Extracellular Matrix
Interleukin-18 Receptors
Collagen
Fibroblasts
Western Blotting
Immunohistochemistry
Caspase 1
Interleukin-8
Keratinocytes

ASJC Scopus subject areas

  • Dermatology

Cite this

Interleukin-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions. / Do, D. V.; Ong, C. T.; Khoo, Y. T.; Carbone, A.; Lim, C. P.; Wang, S.; Mukhopadhyay, A.; Cao, X.; Cho, Dae Ho; Wei, X. Q.; Bellone, G.; Lim, I.; Phan, T. T.

In: British Journal of Dermatology, Vol. 166, No. 6, 01.06.2012, p. 1275-1288.

Research output: Contribution to journalArticle

Do, DV, Ong, CT, Khoo, YT, Carbone, A, Lim, CP, Wang, S, Mukhopadhyay, A, Cao, X, Cho, DH, Wei, XQ, Bellone, G, Lim, I & Phan, TT 2012, 'Interleukin-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions', British Journal of Dermatology, vol. 166, no. 6, pp. 1275-1288. https://doi.org/10.1111/j.1365-2133.2011.10721.x
Do, D. V. ; Ong, C. T. ; Khoo, Y. T. ; Carbone, A. ; Lim, C. P. ; Wang, S. ; Mukhopadhyay, A. ; Cao, X. ; Cho, Dae Ho ; Wei, X. Q. ; Bellone, G. ; Lim, I. ; Phan, T. T. / Interleukin-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions. In: British Journal of Dermatology. 2012 ; Vol. 166, No. 6. pp. 1275-1288.
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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. 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-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.",
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AU - Do, D. V.

AU - Ong, C. T.

AU - Khoo, Y. T.

AU - Carbone, A.

AU - Lim, C. P.

AU - Wang, S.

AU - Mukhopadhyay, A.

AU - Cao, X.

AU - Cho, Dae Ho

AU - Wei, X. Q.

AU - Bellone, G.

AU - Lim, I.

AU - Phan, T. T.

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N2 - 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-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.

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-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.

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