TGF-beta effects on airway smooth muscle cell proliferation, VEGF release and signal transduction pathways.
OBJECTIVE
Airway smooth muscle (ASM) cell hyperplasia is a key feature of airway remodelling. Mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) are key components in signal transduction associated with cell proliferation; MAPK consists of the extracellular signal-regulated kinase (ERK), p38MAPK and c-Jun NH(2)-terminal kinase (JNK). The effect of transforming growth factor (TGF)-beta on the proliferation of ASM cells, the release of vascular endothelial growth factor (VEGF) by ASM cells and relevant signal transduction pathways were investigated.


METHODS
ASM cells were growth-arrested for 48 h then stimulated with platelet-derived growth factor (PDGF), TGF-beta and dexamethasone. ASM cells were also treated with specific inhibitors of MAPK (PD98059), PI3K (wortmannin) and JNK (SP600125). Cell proliferation and VEGF concentrations were measured.


RESULTS
TGF-beta neither augmented ASM cell proliferation nor showed a synergistic effect on PDGF-mediated ASM cell proliferation. Dexamethasone did not suppress ASM cell proliferation. VEGF release was augmented by TGF-beta stimulation in a time-dependent manner, and was further enhanced by co-stimulation with PDGF and TGF-beta. Dexamethasone suppressed VEGF release significantly. TGF-beta enhanced PI3K phosphorylation, while PDGF augmented both ERK and PI3K phosphorylation. Wortmannin inhibited both TGF-beta- and PDGF-stimulated VEGF release.


CONCLUSIONS
TGF-beta may facilitate airway remodelling by promoting VEGF release through the PI3K pathway, rather than via ASM cell proliferation.
Shin
Joo Hwa
JH
Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Shim
Jae Won
JW
Kim
Deok Soo
DS
Shim
Jung Yeon
JY
D000730:Androstadienes / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000166:cytology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D000873:Anthracenes; D005419:Flavonoids; D005938:Glucocorticoids; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C432165:pyrazolanthrone; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin