Epinephrine induces beta-adrenergic desensitization and differentiation of HL-60 cells.
The HL-60 cell line was cultured in a serum-free medium and exposed to various concentrations of EPI. The effects on cell growth, differentiation and beta-adrenergic response were followed during the culture period of 72 h. Short-term exposure (3 min) to EPI (1 nM-1 mM) in the presence of theophylline (4 mM) caused a dose-dependent increase of cAMP levels with a maximum of 1500% above basal levels. When the cells were exposed to EPI (1 nM-10 microM) for 72 h, a dose-dependent increase of cAMP levels with a maximum of 60% above basal levels. Sustained exposure to EPI generated a dose-dependent desensitization of the beta-adrenergic signal system. After EPI treatment for 72 h, IPR (10 microM for 3 min) in the presence of theophylline (4 mM) increased cAMP-levels by only 80% above baseline level (cAMP levels after maintained exposure to EPI), compared to 1080% above unstimulated level in control cells. The alpha-adrenergic receptor blocker PHENT (10 microM) did not affect baseline cAMP level or IPR-dependent cAMP response, but a mixture of EPI and PHENT increased the response to IPR. The HL-60 cell growth was not influenced by EPI. However, after repeated exposure to EPI for 72 h a concentration-dependent increase of HL-60 differentiation was demonstrated. Differentiation was not influenced by PHENT. These results suggest a differentiation induction due to a beta-adrenergic-induced cAMP elevation.
Department of Pharmacology, University of Tromsø, Norway.
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Bang
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Aarbakke
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D000262:Adenylyl Cyclases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D010646:Phentolamine / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases; D004837:Epinephrine; D010646:Phentolamine