Endothelin regulates Porphyromonas gingivalis-induced production of inflammatory cytokines

Ga Yeon Son, Eun Jung Bak, Ji Hye Kim, Dong Eun Lee, Si Mook Kang, So Yun Lee, Lin Choi, Ji Su Sun, Seul Ki Kim, Wonse Park, Baekil Kim, Yun Jung Yoo, Inik Chang, DongMin Shin

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1 Citation (Scopus)

Abstract

Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1β, TNFα, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment.

Original languageEnglish
Article number0167713
JournalPloS one
Volume11
Issue number12
DOIs
Publication statusPublished - 2016 Dec 1

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Porphyromonas gingivalis
endothelins
Periodontitis
Endothelins
Endothelin-1
cytokines
Cytokines
Epithelial Cells
Mouth Diseases
Chemical activation
Endothelin-2
Gingival Crevicular Fluid
Tissue
Alveolar Bone Loss
Endothelin A Receptors
Endothelin Receptors
Inositol 1,4,5-Trisphosphate
epithelial cells
Type C Phospholipases
G-Protein-Coupled Receptors

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Son, Ga Yeon ; Bak, Eun Jung ; Kim, Ji Hye ; Lee, Dong Eun ; Kang, Si Mook ; Lee, So Yun ; Choi, Lin ; Sun, Ji Su ; Kim, Seul Ki ; Park, Wonse ; Kim, Baekil ; Yoo, Yun Jung ; Chang, Inik ; Shin, DongMin. / Endothelin regulates Porphyromonas gingivalis-induced production of inflammatory cytokines. In: PloS one. 2016 ; Vol. 11, No. 12.
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title = "Endothelin regulates Porphyromonas gingivalis-induced production of inflammatory cytokines",
abstract = "Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1β, TNFα, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment.",
author = "Son, {Ga Yeon} and Bak, {Eun Jung} and Kim, {Ji Hye} and Lee, {Dong Eun} and Kang, {Si Mook} and Lee, {So Yun} and Lin Choi and Sun, {Ji Su} and Kim, {Seul Ki} and Wonse Park and Baekil Kim and Yoo, {Yun Jung} and Inik Chang and DongMin Shin",
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Son, GY, Bak, EJ, Kim, JH, Lee, DE, Kang, SM, Lee, SY, Choi, L, Sun, JS, Kim, SK, Park, W, Kim, B, Yoo, YJ, Chang, I & Shin, D 2016, 'Endothelin regulates Porphyromonas gingivalis-induced production of inflammatory cytokines', PloS one, vol. 11, no. 12, 0167713. https://doi.org/10.1371/journal.pone.0167713

Endothelin regulates Porphyromonas gingivalis-induced production of inflammatory cytokines. / Son, Ga Yeon; Bak, Eun Jung; Kim, Ji Hye; Lee, Dong Eun; Kang, Si Mook; Lee, So Yun; Choi, Lin; Sun, Ji Su; Kim, Seul Ki; Park, Wonse; Kim, Baekil; Yoo, Yun Jung; Chang, Inik; Shin, DongMin.

In: PloS one, Vol. 11, No. 12, 0167713, 01.12.2016.

Research output: Contribution to journalArticle

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T1 - Endothelin regulates Porphyromonas gingivalis-induced production of inflammatory cytokines

AU - Son, Ga Yeon

AU - Bak, Eun Jung

AU - Kim, Ji Hye

AU - Lee, Dong Eun

AU - Kang, Si Mook

AU - Lee, So Yun

AU - Choi, Lin

AU - Sun, Ji Su

AU - Kim, Seul Ki

AU - Park, Wonse

AU - Kim, Baekil

AU - Yoo, Yun Jung

AU - Chang, Inik

AU - Shin, DongMin

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1β, TNFα, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment.

AB - Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1β, TNFα, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment.

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