Chronic terbutaline treatment desensitizes β‐adrenergic inhibition of lymphocyte activation in healthy volunteers

Abstract

1. A substantial body of evidence has accumulated that beta-adrenoceptor mediated increases in human lymphocyte cyclic AMP can inhibit activation of resting lymphocytes. The aim of this study was to determine whether this effect might desensitize during chronic beta-adrenoceptor agonist treatment. We assessed the effects of 2 weeks treatment with the beta 2-adrenoceptor agonist terbutaline (3 x 5 mg day-1 p.o.) on isoprenaline-induced inhibition of concanavalin A-evoked lymphocyte activation in nine healthy male volunteers. Lymphocyte activation was determined by [3H]-thymidine incorporation (as a measure of proliferation), and inositol phosphate formation was assessed in [3H]-myo-inositol prelabelled lymphocytes in the presence of 10 mM LiCl. 2. Terbutaline treatment caused a significant reduction in isoprenaline (1 nM-10 microM)-induced increases in lymphocyte cyclic AMP content; the maximal increase was 14 +/- 3 pmol/10(6) cells before and 7 +/- 2 pmol/10(6) cells (n = 9, P < 0.05) after terbutaline treatment. 3. The mitogen concanavalin A (Con A, 1-32 micrograms ml-1)-induced increase in inositol phosphate formation was significantly enhanced after terbutaline treatment (max. increase before treatment: 255 +/- 25% above basal; after treatment 453 +/- 16% above basal; n = 9, P < 0.001), while isoprenaline (1 nM-10 microM)-induced inhibition of Con A (16 micrograms ml-1)-evoked increases in inositol phosphate formation was significantly reduced after the terbutaline treatment (max. inhibition before treatment: 22 +/- 4%; after treatment 9 +/- 1%, n = 9, P < 0.01). 4. Con A (1.25-10 micrograms ml-1)-induced increases in [3H]-thymidine incorporation into the lymphocytes (as a measure of proliferation) was not affected by the terbutaline treatment. On the other hand, isoprenaline (1 nM-1 microM)-induced inhibition of Con A (5 micrograms ml-1)-evoked lymphocyte proliferation (max. inhibition: 33 +/- 7%, n = 9) was almost completely abolished after the terbutaline treatment. 5. We conclude that chronic treatment with terbutaline desensitizes lymphocyte beta 2-adrenoceptors and, therefore, the inhibitory effect of cyclic AMP on lymphocyte activation.

Effects of 6-Hydroxydopamine on the Development of the Immune System in Chickens.

“…Chronic β-adrenergic agonist treatment decreased β-AR density of lymphocyte [44]. However, in this study, NE level was not involved in decreased expression of β-AR mRNA, because no increase of NE levels both in the spleen and plasma was observed.…”

Activation of β₃ Adrenergic Receptor Decreases DNA synthesis in Human Skin Fibroblasts Via Cyclic GMP/Nitric Oxide Pathway

“…The positive action has been observed on human cardiac fibroblasts [7][8][9] and the negative action was previously reported on human lymphocytes [10]. The human β 2 adrenoceptor stimulation has been the prototype for elucidating mechanisms of human fibroblast proliferation [11].…”

Genotype-dependent time course of lymphocyte β2-adrenergic receptor down-regulation

“…The lymphocyte interphase was carefully removed, washed with PBS by centrifugation at 750 g for 10 minutes (20°C) and at 620 g for 10 minutes (20°C), and finally resuspended either in 10‐mmol/L Tris–hydrochloric acid and 154‐mmol/L sodium chloride buffer (pH 7.4) containing 30‐μmol/L phentolamine hydrochloride (INN, phentolamine), 0.55‐mmol/L ascorbic acid, and 2 mg/100 mL bovine serum albumin (for binding studies) or in PBS containing 100‐μmol/L isobutylmethylxanthine (for cyclic AMP determination). Details have been described previously 7 , 12 …”

“…Lymphocyte cyclic AMP accumulation was determined as previously described 12 . In brief, 300‐μL (2 × 10 6 cells) aliquots were incubated for 15 minutes at 37°C in the presence or absence of (−)‐isoproterenol (1 nmol/L to 1 μmol/L; Sigma, Deisenhofen, Germany) in a total volume of 330 μL.…”

“…Details have been described previously. 7,12 ␤ 2 AR density ␤ 2 AR density in human lymphocytes was determined as detailed previously. 7 In brief, lymphocytes (0.5 ϫ 10 6 cells/tube) were incubated for 90 minutes with 6 concentrations of ICYP ranging from 10 to 200 pmol/L at 37°C in a total volume of 250 L. Incubation was terminated by diluting the entire reaction mixture with 10-mmol/L Tris-hydrochloric acid and 154mmol/L sodium chloride (pH 7.4), followed by rapid filtration over Whatman GF/C filters (Whatman, Inc, Clifton, NJ).…”