beta2-Adrenoceptor agonists enhance cytokine-induced release of thymic stromal lymphopoietin by lung tissue cells.

Abstract

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.

• Authors: Kyoko Futamura, Kanami Orihara, Noriko Hashimoto, Hideaki Morita, Shuhei Fukuda, Hironori Sagara, Kenji Matsumoto, Yasushi Tomita, Hirohisa Saito, Akio Matsuda
• Journal: International archives of allergy and immunology (Int Arch Allergy Immunol) Vol. 152 Issue 4 Pg. 353-61 ( 2010) ISSN: 1423-0097 [Electronic] Switzerland
• PMID: 20185927 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 S. Karger AG, Basel.

Chemical References

• Adrenergic beta-Agonists
• Androstadienes
• Bronchodilator Agents
• Cytokines
• Tumor Necrosis Factor-alpha
• Interleukin-4
• Fluticasone
• Cyclic AMP
• Thymic Stromal Lymphopoietin

Topics

• Adrenergic beta-Agonists (pharmacology)
• Androstadienes (pharmacology)
• Asthma (drug therapy)
• Bronchodilator Agents (pharmacology)
• Cells, Cultured
• Cyclic AMP (metabolism)
• Cytokines (biosynthesis, genetics)
• Drug Therapy, Combination
• Fibroblasts (drug effects, metabolism, pathology)
• Fluticasone
• Humans
• Interleukin-4 (metabolism)
• Lung (metabolism, pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Respiratory Mucosa (drug effects, metabolism, pathology)
• Tumor Necrosis Factor-alpha (metabolism)
• Thymic Stromal Lymphopoietin