Epinephrine induces β-adrenergic desensitization and differentiation of HL-60 cells

Abstract

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.

Second-messenger regulation of receptor association with clathrin-coated pits: a novel and selective mechanism in the control of CD4 endocytosis.

“…Already relatively small 2 The method used does not allow us to obtain absolute values for cellular cAMP levels. However, previous studies in granulocytes have demonstrated basal cAMP levels of 1-3 pmol/106 cells (Prytz et al, 1991;Bang et al, 1993 Thus, our data demonstrate that cAMP blocks CD4 endocytosis, as 1) all compounds that raised cAMP blocked CD4 endocytosis and 2) there was an all-over relationship between the cAMP levels and the inhibition of CD4 endocytosis. We next investigated whether the physiological receptor agonist PGE1, which is known to raise cAMP myeloid cells (Scott, 1970;Bourne et al, 1971), also had effects on CD4 endocytosis.…”

Effects of CAMP and cGMP Elevating Agents on HL‐60 Cell Differentiation

“…Theophylline, caffeine and isobutylmethylxanthine act as non-specific inhibitors of phosphodiesterase isoenzymes (Nicholson et al 1991 Previous studies in our laboratory have demonstrated a reduction in the expression of the nuclear oncogenes, c-fos and c-myc in HL-60 cells, after exposure to theophylline and theophylline plus isoproterenol (Moens et al 1990). We have also observed a modest degree of HL-60 cell differentiation after cAMP stimulation through P-adrenergic receptors (Bang et al 1993). The cGMP levels in this study were, however, not measured.…”

Reduced beta adrenoceptor density in vivo in human lung tumours: a preliminary study with positron emission tomography.

“…4 In addition, in vivo administration of the 1 agonist isoprenaline in rat resulted in a suppression of the growth of the C-6 glioma tumour,' while ablation of the sympathetic nerve system augmented tumour growth.5 Furthermore, this suppressive response of isoprenaline was proportional to the 1 adrenergic receptor density on the tumour cell surface.6 Reduced density of 13 adrenergic receptors in tumour tissue has been previously reported in in vitro studies. Mouse lymphocytic leukaemia cells have been shown to have fewer 1 adrenoceptors per cell and a smaller fraction of these receptors are functionally active cell surface receptors.7 In lung, mouse neoplastic cells contained fewer 1 adrenoceptors and produced less cAMP in response to isoprenaline.8 In human lung in vitro 13 receptors were also decreased in cancer tissue.…”