Role of cyclic AMP in the modulation of IgE production by the beta 2-adrenoceptor agonist, fenoterol.
We have previously demonstrated that the beta 2-adrenoceptor agonist, salbutamol, potentiates the effect of interleukin-4 (IL-4) on immunoglobulin E (IgE) production by human peripheral blood mononuclear cells (PBMC). This study was undertaken to further define the activities of these drugs and the role of cyclic-adenosine monophosphate (cAMP) in the modulation of IgE production. Our results indicate that fenoterol (1 microM) potentiated IL-4-induced IgE production and IgE messenger ribonucleic acid (mRNA) expression. Moreover, this effect was associated with an increase in intracellular cAMP levels. The activities of this drug on IgE production were mimicked by cell permeable cAMP analogues, such as dibutyryl-cAMP (db-cAMP) (100 microM) or Sp-AMP (10 microM). The potentiating effect of fenoterol on IgE production was markedly inhibited in the presence of protein kinase A (PKA) inhibitors: H8 (10 microM) and Rp-AMP (10 microM), suggesting that its effects are likely to depend on the activation of the cAMP pathway. Additionally, the potentiating effect of fenoterol was also blocked in the presence of indomethacin. Fenoterol potentiated IL-4-induced IgE production from purified B-cells activated through their CD40 antigen. This effect was associated with an increase in cellular viability. Therefore, the activities of this drug on PBMC are likely to be mediated by the activation of another cellular type. Taken together, these results show that fenoterol potentiates the IL-4-induced IgE production via the cAMP pathway, but that this enhancement could not be explained by a direct effect on B-lymphocytes.
Coqueret
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O
Département d'Immunologie, Institut Henri Beaufour, Les Ulis, France.
Demarquay
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D
Lagente
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V
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005280:Fenoterol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000235:genetics; D007213:Indomethacin / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis
D000318:Adrenergic beta-Agonists; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D015847:Interleukin-4; D005280:Fenoterol; D007073:Immunoglobulin E; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007213:Indomethacin