Abstract
Exposure to cigarette smoke extract (CSE) leads to airway or lung inflammation, which may be mediated through cyclooxygenase-2 (COX-2) expression and its product prostaglandin E2 (PGE2) synthesis. The aim of this study was to investigate the molecular mechanisms underlying CSE-induced COX-2 expression in human tracheal smooth muscle cells (HTSMCs). Here, we describe that COX-2 induction is dependent on PKCα/c-Src/EGFR, PDGFR/PI3K/Akt/NF-κB signaling in HTSMCs. CSE stimulated the phosphorylation of c-Src, EGFR, PDGFR, and Akt, which were inhibited by pretreatment with the inhibitor of PKCα (Gö6976 or Gö6983), c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), or PI3K (LY294002). Moreover, CSE induced a significant increase in COX-2 expression, which was reduced by pretreatment with these inhibitors or transfection with siRNA of PKCα, Src, or Akt. Furthermore, CSE-stimulated NF-κB p65 phosphorylation and translocation were also attenuated by pretreatment with Gö6976, PP1, AG1478, AG1296, or LY294002. CSE-induced COX-2 expression was also mediated through the recruitment of p300 associated with NF-κB in HTSMCs, revealed by coimmunoprecipitation and Western blot analysis. In addition, pretreatment with the inhibitors of NF-κB (helenalin) and p300 (garcinol) or transfection with p65 siRNA and p300 siRNA markedly inhibited CSE-regulated COX-2 expression. However, CSE-induced PGE2 generation was reduced by pretreatment with the inhibitor of COX-2 (NS-398). These results demonstrated that in HTSMCs, CSE-induced COX-2-dependent PGE2 generation was mediated through PKCα/c-Src/EGFR, PDGFR/PI3K/Akt leading to the recruitment of p300 with NF-κB complex.
| Original language | English |
|---|---|
| Pages (from-to) | L892-L902 |
| Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
| Volume | 297 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Nov 1 2009 |
| Externally published | Yes |
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Keywords
- Airway inflammation
- Cyclooxygenase-2
- Human
- Prostaglandin E
ASJC Scopus subject areas
- Physiology
- Pulmonary and Respiratory Medicine
- Cell Biology
- Physiology (medical)
Cite this
Cigarette smoke extract induces COX-2 expression via a PKCα/c-Src/ EGFR, PDGFR/PI3K/Akt/NF-κB pathway and p300 in tracheal smooth muscle cells. / Yang, Chuen Mao; Lee, I. Ta; Lin, Chih Chung; Yang, Ya Lin; Luo, Shue Fen; Kou, Yu Ru; Hsiao, Li Der.
In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 297, No. 5, 01.11.2009, p. L892-L902.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cigarette smoke extract induces COX-2 expression via a PKCα/c-Src/ EGFR, PDGFR/PI3K/Akt/NF-κB pathway and p300 in tracheal smooth muscle cells
AU - Yang, Chuen Mao
AU - Lee, I. Ta
AU - Lin, Chih Chung
AU - Yang, Ya Lin
AU - Luo, Shue Fen
AU - Kou, Yu Ru
AU - Hsiao, Li Der
PY - 2009/11/1
Y1 - 2009/11/1
N2 - Exposure to cigarette smoke extract (CSE) leads to airway or lung inflammation, which may be mediated through cyclooxygenase-2 (COX-2) expression and its product prostaglandin E2 (PGE2) synthesis. The aim of this study was to investigate the molecular mechanisms underlying CSE-induced COX-2 expression in human tracheal smooth muscle cells (HTSMCs). Here, we describe that COX-2 induction is dependent on PKCα/c-Src/EGFR, PDGFR/PI3K/Akt/NF-κB signaling in HTSMCs. CSE stimulated the phosphorylation of c-Src, EGFR, PDGFR, and Akt, which were inhibited by pretreatment with the inhibitor of PKCα (Gö6976 or Gö6983), c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), or PI3K (LY294002). Moreover, CSE induced a significant increase in COX-2 expression, which was reduced by pretreatment with these inhibitors or transfection with siRNA of PKCα, Src, or Akt. Furthermore, CSE-stimulated NF-κB p65 phosphorylation and translocation were also attenuated by pretreatment with Gö6976, PP1, AG1478, AG1296, or LY294002. CSE-induced COX-2 expression was also mediated through the recruitment of p300 associated with NF-κB in HTSMCs, revealed by coimmunoprecipitation and Western blot analysis. In addition, pretreatment with the inhibitors of NF-κB (helenalin) and p300 (garcinol) or transfection with p65 siRNA and p300 siRNA markedly inhibited CSE-regulated COX-2 expression. However, CSE-induced PGE2 generation was reduced by pretreatment with the inhibitor of COX-2 (NS-398). These results demonstrated that in HTSMCs, CSE-induced COX-2-dependent PGE2 generation was mediated through PKCα/c-Src/EGFR, PDGFR/PI3K/Akt leading to the recruitment of p300 with NF-κB complex.
AB - Exposure to cigarette smoke extract (CSE) leads to airway or lung inflammation, which may be mediated through cyclooxygenase-2 (COX-2) expression and its product prostaglandin E2 (PGE2) synthesis. The aim of this study was to investigate the molecular mechanisms underlying CSE-induced COX-2 expression in human tracheal smooth muscle cells (HTSMCs). Here, we describe that COX-2 induction is dependent on PKCα/c-Src/EGFR, PDGFR/PI3K/Akt/NF-κB signaling in HTSMCs. CSE stimulated the phosphorylation of c-Src, EGFR, PDGFR, and Akt, which were inhibited by pretreatment with the inhibitor of PKCα (Gö6976 or Gö6983), c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), or PI3K (LY294002). Moreover, CSE induced a significant increase in COX-2 expression, which was reduced by pretreatment with these inhibitors or transfection with siRNA of PKCα, Src, or Akt. Furthermore, CSE-stimulated NF-κB p65 phosphorylation and translocation were also attenuated by pretreatment with Gö6976, PP1, AG1478, AG1296, or LY294002. CSE-induced COX-2 expression was also mediated through the recruitment of p300 associated with NF-κB in HTSMCs, revealed by coimmunoprecipitation and Western blot analysis. In addition, pretreatment with the inhibitors of NF-κB (helenalin) and p300 (garcinol) or transfection with p65 siRNA and p300 siRNA markedly inhibited CSE-regulated COX-2 expression. However, CSE-induced PGE2 generation was reduced by pretreatment with the inhibitor of COX-2 (NS-398). These results demonstrated that in HTSMCs, CSE-induced COX-2-dependent PGE2 generation was mediated through PKCα/c-Src/EGFR, PDGFR/PI3K/Akt leading to the recruitment of p300 with NF-κB complex.
KW - Airway inflammation
KW - Cyclooxygenase-2
KW - Human
KW - Prostaglandin E
UR - http://www.scopus.com/inward/record.url?scp=72449143164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=72449143164&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00151.2009
DO - 10.1152/ajplung.00151.2009
M3 - Article
C2 - 19717552
AN - SCOPUS:72449143164
VL - 297
SP - L892-L902
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 1040-0605
IS - 5
ER -