Differential regulation of transforming growth factor-beta receptors type I and II by platelet-derived growth factor in human dermal fibroblasts.
BACKGROUND
Elevated expression of platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta have been observed in a number of fibrotic diseases, including systemic sclerosis (SSc). This suggests a possible interaction between these factors in establishing a profibrotic programme in dermal fibroblasts.


OBJECTIVE
To examine the effects of PDGF isoforms on the expression of TGF-beta receptors in human dermal fibroblasts.


METHODS
Steady-state mRNA levels of TGF-beta receptor I and II (TbetaR-I and TbetaR-II) were analysed by northern blot. TbetaR-I protein levels were analysed by immunoprecipitation of 35S metabolically labelled cells. TbetaR-II protein levels were analysed by western blot.


RESULTS
Steady-state mRNA levels of TbetaR-I and TbetaR-II were induced in response to PDGF isoforms. PDGF-AA and PDGF-AB stimulated both receptors with similar potency, whereas PDGF-BB was less potent. The MEK1 (mitogen-activated protein kinase [MAPK] or extracellular signal regulated kinase) inhibitor, PD98059, abrogated the stimulatory effect of PDGF-AB. In contrast to mRNA levels, only TbetaR-II protein levels were elevated in response to PDGF.


CONCLUSIONS
These data suggest that PDGF receptor alpha and MAPK mediate stimulation of TGF-beta receptors by PDGF. Furthermore, TGF-beta receptor protein levels are discordantly regulated by PDGF.
Czuwara-Ladykowska
J
J
Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas St, Suite 912, Charleston, SC 29401, USA.
Gore
E A
EA
Shegogue
D A
DA
Smith
E A
EA
Trojanowska
M
M
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D005347:Fibroblasts / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D005419:Flavonoids; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one