ET-1 cooperates with EGF to induce mitogenesis via a PTX-sensitive pathway in airway smooth muscle cells.
We have examined the mitogenic effect of endothelin-1 (ET-1) alone or in combination with epidermal growth factor (EGF) in cultured airway smooth muscle cells (ASM) from guinea pig. ET-1 showed a weak mitogenic activity compared with the effect of EGF. However, when ET-1 and EGF were applied simultaneously, ET-1 synergistically enhanced the mitogenic activity of EGF. Neither inhibition of phospholipase C-beta nor depletion of protein kinase C affected this synergism. On the other hand, pertussis toxin (PTX), a Gi protein inhibitor, abolished the synergistic effect of ET-1 on EGF-induced mitogenesis. ET-1 induced a transient mitogen-activated protein (MAP) kinase activation peaking at 5 min. In contrast, EGF induced a stronger signal that was maintained for up to 20 min. However, concomitant stimulation of ASM with ET-1 and EGF caused an enhanced MAP kinase activation compared with EGF alone. Moreover, PTX abolished the enhanced MAP kinase activation observed in this condition. These results indicate that ET-1 can interact with an EGF-induced mitogenic axis through the Gi protein-dependent pathway, which is distinct from its direct mitogenic pathway.
Fujitani
Y
Y
Department of Respiratory Diseases and Allergy, Ciba-Geigy Limited, Basel, Switzerland.
Bertrand
C
C
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004338:Drug Combinations; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006168:Guinea Pigs; D008938:Mitosis / Q000187:drug effects*; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D037342:Pertussis Toxin; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017466:Receptors, Endothelin / Q000378:metabolism; D014132:Trachea / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D004338:Drug Combinations; D019332:Endothelin-1; D017466:Receptors, Endothelin; D010566:Virulence Factors, Bordetella; D004815:Epidermal Growth Factor; D037342:Pertussis Toxin; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases