Inhibitory activity of fenoterol on Dermatophagoides-, Parietaria-, tetanus-toxoid-, and Candida albicans-stimulated blood mononuclear cells: differences in beta2-adrenoreceptor stimulation but not in cell apoptosis.
beta2-adrenoreceptor agonists have the ability to downregulate in vitro the proliferative response of peripheral blood mononuclear cells (BMCs). This activity could be related to a variety of beta2-adrenoreceptor-mediated functions, including induction of cell apoptosis in activated T-cells. To test this hypothesis, BMCs from atopic subjects, sensitized to house dust mites (Dermatophagoides [Der p]) and/or to Parietaria were incubated with fenoterol (10(-8)-10(-5) M) in the presence of (a) purified allergen extracts (Der p [5 microg/mL] or Parietaria [5 microg/mL]) or (b) antigens (tetanus toxoid [1 microg/mL] or Candida albicans [5 x 10(5) bodies/mL]). The BMC proliferation was assessed by [3H] thymidine incorporation and cell apoptosis was assessed by evaluating DNA fragmentation by a fluorescence technique, using propidium iodide. In cultures stimulated with Der p or with Parietaria, fenoterol induced a dose-dependent inhibition of BMC proliferation, significant also at the lowest concentration tested (10(-8) M) (p < 0.05, each comparison). In contrast, the inhibitory activity of the drug on tetanus-toxoid-stimulated BMCs was significant only at the highest dose tested (10(-5)M) (p < 0.05), whereas no effect was seen when BMCs were stimulated with C. albicans extract (p > 0.05). The different inhibitory efficacy of fenoterol appeared to be related to the degree of activation of beta2-adrenoreceptors on the different BMC populations that responded to the different stimuli. Indeed, in the presence of fenoterol (10(-6) and 10(-5)M), a significant increase in cyclic adenosine monophosphate (cAMP) levels was seen in Der p- or Parietaria-stimulated cells (p < 0.05; each comparison), but not in cell cultures stimulated with tetanus toxoid or with C. albicans extracts (p > 0.05; each comparison). Finally, the percentage of cells with fragmented DNA was lower in cultures stimulated with Der p or Parietaria than in those stimulated with tetanus toxoid or C. albicans, and the presence of fenoterol did not modify cell apoptosis (p > 0.05; each comparison). Thus, the different inhibitory activity of fenoterol on BMCs activated by allergens (Der p or Parietaria) or by antigens (tetanus toxoid or C. albicans) seems to be related to differences in beta2-adrenoreceptor expression and/or function in the different antigen-specific T-cell subsets, but it is not influenced by changes in cell apoptosis.
Silvestri
M
M
Divisione di Pneumologia, Istituto G. Gaslini, Genova, Italy.
Oddera
S
S
Scarso
L
L
Pistoia
V
V
Tasso
P
P
Rossi
G A
GA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000485:Allergens / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002176:Candida albicans / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005280:Fenoterol / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008925:Mites / Q000276:immunology; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013745:Tetanus Toxoid / Q000276:immunology
D000318:Adrenergic beta-Agonists; D000485:Allergens; D018343:Receptors, Adrenergic, beta-2; D013745:Tetanus Toxoid; D005280:Fenoterol; D000242:Cyclic AMP