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A_2B Adenosine Receptors Increase Cytokine Release by Bronchial Smooth Muscle Cells

Department of Drug Research and Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, California; and Department of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee

Address correspondence to: Dewan Zeng, Ph.D., CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: dewan.zeng{at}cvt.com

Adenosine (Ado) has been suggested to play a role in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. The goal of this study was to determine the effect of Ado and its receptor subtypes on cytokine release by bronchial smooth muscle cells. The A_2B Ado receptor (AdoR) was expressed at the highest level among the four AdoR subtypes. Activation of the A_2B AdoR by an Ado analog, 5'-(N-ethylcarboxamido)-adenosine (NECA), increased cAMP accumulation with potency (EC₅₀ value) of 21.2 ± 0.2 µM. The effect of NECA on the expression of the inflammatory cytokines was determined using a cDNA array consisting of 23 cytokine genes and confirmed using real-time reverse transcription–polymerase chain reaction and enzyme-linked immunosorbent assay. NECA increased the release of interleukin-6 and monocyte chemotactic protein-1 proteins with EC₅₀ values of 1.26 ± 0.25 µM and 0.40 ± 0.08 µM, respectively, and the maximal folds of induction were 20.8 ± 1.7– and 6.4 ± 0.7–fold, respectively. Selective agonists for the A₁, A_2A, and A₃ AdoR subtypes had no effect on cytokine release. The effects of NECA were attenuated by selective antagonists of the A_2B AdoR. Thus, Ado increases the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells via activation of the A_2B AdoR. Our findings provide a novel mechanism whereby Ado acts as a proinflammatory mediator in the airway.

Abbreviations: adenosine, Ado • adenosine receptor, AdoR • activator protein-1, AP-1 • bronchial smooth muscle cell, BSMC • 2-p-(2-Carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine, CGS-21680 • chronic obstructive pulmonary disease, COPD • N⁶-cyclopentyladenosine, CPA • cAMP responsive element-binding protein, CREB • dibutyryl cAMP, DBcAMP • enzyme-linked immunosorbent assay, ELISA • N⁶-(3-iodobenzyl)-adenosine-5'-N-methyluronamide, IB-MECA • interleukin, IL • 3-isobutyl-8-pyrrolidinoxanthine, IPDX • monocyte chemotactic protein-1, MCP-1 • 5'-(N-ethylcarboxamido)-adenosine, NECA • nuclear factor B, NF-B • nuclear factor of activated T cells, NFAT • reverse transcription–polymerase chain reaction, RT-PCR • transforming growth factor, TGF

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