beta2-Adrenoceptor agonists enhance cytokine-induced release of thymic stromal lymphopoietin by lung tissue cells.
BACKGROUND
Whilebeta(2)-adrenoceptor agonists (beta(2)-agonists) are widely used as bronchodilators in the treatment of asthma, there has been increasing concern that regular use of beta(2)-agonists may adversely affect the control of asthma. However, the molecular mechanisms of such undesirable effects of beta(2)-agonists are not fully understood. In this study, we examined the effects of beta(2)-agonists on cytokine-induced production of thymic stromal lymphopoietin (TSLP), an indispensable cytokine in the development of allergic diseases, by lung tissue cells.


METHODS
Normal human bronchial epithelial cells (NHBE), smooth muscle cells (BSMC) and fibroblasts (NHLF) were stimulated with the IL-4 and TNF-alpha cytokines, alone and in combination, and their production of TSLP was examined by ELISA. The effects of beta(2)-agonists (salmeterol, formoterol, salbutamol), intracellular cyclic adenosine monophosphate (cAMP)-elevating agents (8-bromo-cAMP, dibutyryl cAMP, forskolin) and a corticosteroid (fluticasone) on the cytokine-induced TSLP production were examined.


RESULTS
The following results were observed in all three types of lung tissue cells tested (that is, NHBE, BSMC and NHLF). Costimulation with IL-4 and TNF-alpha significantly induced TSLP production, and beta(2)-agonists further enhanced it via upregulation of intracellular cAMP. However, addition of a corticosteroid to the cytokines and beta(2)-agonist resulted in a marked decrease in TSLP production.


CONCLUSIONS
beta(2)-Agonists significantly enhanced the cytokine-induced TSLP production by primary human lung tissue cells. This may be partly responsible for the undesirable clinical effects of continuous beta(2)-agonist monotherapy, and combination therapy with a corticosteroid might effectively inhibit TSLP-mediated allergic inflammation.
Futamura
Kyoko
K
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Orihara
Kanami
K
Hashimoto
Noriko
N
Morita
Hideaki
H
Fukuda
Shuhei
S
Sagara
Hironori
H
Matsumoto
Kenji
K
Tomita
Yasushi
Y
Saito
Hirohisa
H
Matsuda
Akio
A
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004359:Drug Therapy, Combination; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000068298:Fluticasone; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D001993:Bronchodilator Agents; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D000068298:Fluticasone; D000242:Cyclic AMP; D000094632:Thymic Stromal Lymphopoietin