Thrombin induces ICAM-1 expression in human lung epithelial cells via c-Src/PDGFR/PI3K/ Akt-dependent NF-κB/p300 activation

Shin Ei Cheng, I-Ta Lee, Chih Chung Lin, Li Der Hsiao, Chuen Mao Yang

Research output: Contribution to journalArticle

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Abstract

Up-regulation of ICAM-1 (intercellular adhesion molecule-1) is frequently implicated in lung inflammation and lung diseases, such as IPF (idiopathic pulmonary fibrosis). Thrombin has been shown to play a key role in inflammation via the induction of adhesion molecules, which then causes lung injury. However, the mechanisms underlying thrombin-induced ICAM-1 expression in HPAEpiCs (human pulmonary alveolar epithelial cells) remain unclear. In the present study, we have shown that thrombin induced ICAM-1 expression in HPAEpiCs. Pre-treatment with the inhibitor of thrombin [PPACK (D-Phe-Pro-Arg-chloromethyl ketone)], c-Src (PP1), PDGFR (platelet-derived growth factor receptor) (AG1296), PI3K (phosohinositide 3-kinase) (LY294002), NF-κB (nuclear factor κB) (Bay11-7082) or p300 (GR343) and transfection with siRNAs of c-Src, PDGFR, Akt, p65 and p300 markedly reduced thrombin-induced ICAM-1 expression and monocyte adherence to HPAEpiCs challenged with thrombin. In addition, we established that thrombin stimulated the phosphorylation of c-Src, PDGFR, Akt and p65, which were inhibited by pre-treatment with their respective inhibitors PP1, AG1296, LY294002 or Bay11-7082. In addition, thrombin also enhanced Akt and NF-κB translocation from the cytosol to the nucleus, which was reduced by PP1, AG1296 or LY294002. Thrombin induced NF-κB promoter activity and the formation of the p65-Akt-p300 complex, which were inhibited by AG1296, LY294002 or PP1. Finally, we have shown that thrombin stimulated in vivo binding of p300, Akt and p65 to the ICAM-1 promoter, which was reduced by AG1296, LY294002, SH-5 or PP1. These results show that thrombin induced ICAM-1 expression and monocyte adherence via a c-Src/PDGFR/PI3K/Akt/NF-κB-dependent pathway in HPAEpiCs. Increased understanding of the signalling mechanisms underlying ICAM-1 gene regulation will create opportunities for the development of anti-inflammatory therapeutic strategies.

Original languageEnglish
Pages (from-to)171-183
Number of pages13
JournalClinical Science
Volume127
Issue number3
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

Fingerprint

Platelet-Derived Growth Factor Receptors
Complement Factor B
Intercellular Adhesion Molecule-1
Thrombin
Phosphotransferases
Epithelial Cells
Lung
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Alveolar Epithelial Cells
Monocytes
Idiopathic Pulmonary Fibrosis
Lung Injury
Cytosol
Lung Diseases
Transfection
Pneumonia
Anti-Inflammatory Agents
Up-Regulation
Phosphorylation
6,7-dimethoxy-3-phenylquinoxaline

Keywords

  • Adhesion molecule
  • Lung inflammation
  • Signalling pathway
  • Thrombin
  • Transcription factor

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Thrombin induces ICAM-1 expression in human lung epithelial cells via c-Src/PDGFR/PI3K/ Akt-dependent NF-κB/p300 activation. / Cheng, Shin Ei; Lee, I-Ta; Lin, Chih Chung; Hsiao, Li Der; Yang, Chuen Mao.

In: Clinical Science, Vol. 127, No. 3, 01.01.2014, p. 171-183.

Research output: Contribution to journalArticle

Cheng, Shin Ei ; Lee, I-Ta ; Lin, Chih Chung ; Hsiao, Li Der ; Yang, Chuen Mao. / Thrombin induces ICAM-1 expression in human lung epithelial cells via c-Src/PDGFR/PI3K/ Akt-dependent NF-κB/p300 activation. In: Clinical Science. 2014 ; Vol. 127, No. 3. pp. 171-183.
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abstract = "Up-regulation of ICAM-1 (intercellular adhesion molecule-1) is frequently implicated in lung inflammation and lung diseases, such as IPF (idiopathic pulmonary fibrosis). Thrombin has been shown to play a key role in inflammation via the induction of adhesion molecules, which then causes lung injury. However, the mechanisms underlying thrombin-induced ICAM-1 expression in HPAEpiCs (human pulmonary alveolar epithelial cells) remain unclear. In the present study, we have shown that thrombin induced ICAM-1 expression in HPAEpiCs. Pre-treatment with the inhibitor of thrombin [PPACK (D-Phe-Pro-Arg-chloromethyl ketone)], c-Src (PP1), PDGFR (platelet-derived growth factor receptor) (AG1296), PI3K (phosohinositide 3-kinase) (LY294002), NF-κB (nuclear factor κB) (Bay11-7082) or p300 (GR343) and transfection with siRNAs of c-Src, PDGFR, Akt, p65 and p300 markedly reduced thrombin-induced ICAM-1 expression and monocyte adherence to HPAEpiCs challenged with thrombin. In addition, we established that thrombin stimulated the phosphorylation of c-Src, PDGFR, Akt and p65, which were inhibited by pre-treatment with their respective inhibitors PP1, AG1296, LY294002 or Bay11-7082. In addition, thrombin also enhanced Akt and NF-κB translocation from the cytosol to the nucleus, which was reduced by PP1, AG1296 or LY294002. Thrombin induced NF-κB promoter activity and the formation of the p65-Akt-p300 complex, which were inhibited by AG1296, LY294002 or PP1. Finally, we have shown that thrombin stimulated in vivo binding of p300, Akt and p65 to the ICAM-1 promoter, which was reduced by AG1296, LY294002, SH-5 or PP1. These results show that thrombin induced ICAM-1 expression and monocyte adherence via a c-Src/PDGFR/PI3K/Akt/NF-κB-dependent pathway in HPAEpiCs. Increased understanding of the signalling mechanisms underlying ICAM-1 gene regulation will create opportunities for the development of anti-inflammatory therapeutic strategies.",
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