TGF-beta 1 modulates beta-adrenergic receptor number and function in cultured human tracheal smooth muscle cells.
Pretreatment of cultured human tracheal smooth muscle cells with transforming growth factor-beta 1 (TGF-beta 1) decreased adenosine 3',5'-cyclic monophosphate (cAMP) accumulation by intact cells stimulated with the beta-adrenergic agonist isoproterenol. The maximal inhibition of isoproterenol-stimulated cAMP accumulation by TGF-beta 1 was 31 +/- 3%, and the mean effective concentration (EC50) of TGF-beta 1 was approximately 1.5 pM. TGF-beta 1 decreased the maximal response to isoproterenol but did not change the EC50 value of isoproterenol. TGF-beta 1 did not change cAMP accumulation stimulated by forskolin. TGF-beta 1 pretreatment decreased isoproterenol-stimulated adenylyl cyclase activity measured in broken cell preparations, but did not change the fluoride-stimulated adenylyl cyclase activity. Together these results suggest that the TGF-beta 1 effect is not by direct inhibition of adenylyl cyclase or by decreased activity of the stimulatory GTP-binding protein. Saturation binding experiments with the beta-adrenergic receptor radioligand [125I]iodopindolol showed that TGF-beta 1 pretreatment decreased the beta-adrenergic receptor number. The protein synthesis inhibitor cycloheximide abolished the effect of TGF-beta 1 on both cAMP accumulation and on beta-adrenergic receptor number, indicating that protein synthesis is involved. These results suggest that TGF-beta 1 in the lung could play a role in changing the responsiveness of airway smooth muscle cells to endogenous catecholamines and to beta-adrenergic agonists used in therapy.
Nogami
M
M
Department of Internal Medicine, University of Nebraska Medical Center, Omaha 68198.
Romberger
D J
DJ
Rennard
S I
SI
Toews
M L
ML
D000262:Adenylyl Cyclases / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D005459:Fluorides / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism*; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D011943:Receptors, Adrenergic, beta; D016212:Transforming Growth Factor beta; D003513:Cycloheximide; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D005459:Fluorides