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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/L505    most recent 00046.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kaur, M. Articles by Giembycz, M. A. Search for Related Content PubMed PubMed Citation Articles by Kaur, M. Articles by Giembycz, M. A.

Effect of β₂-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A

Departments of ¹Cell Biology and Anatomy and ²Pharmacology and Therapeutics, Airway Inflammation Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; ³Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and ⁴Respiratory Research Group Faculty of Pharmacy, University of Sydney, New South Wales, Australia

Submitted 24 January 2008 ; accepted in final form 23 June 2008

In diseases such as asthma, airway smooth muscle (ASM) cells play a synthetic role by secreting inflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, or IL-8 and by expressing surface adhesion molecules, including ICAM-1. In the present study, PGE₂, forskolin, and short-acting (salbutamol) and long-acting (salmeterol and formoterol) β₂-adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1β in ASM cells. IL-1β-induced IL-8 release was also repressed by PGE₂ and forskolin, whereas the β₂-adrenoceptor agonists were ineffective. In each case, repression of these inflammatory indexes was prevented by adenoviral overexpression of PKI, a highly selective PKA inhibitor. These data indicate a PKA-dependent mechanism of repression and suggest that agents that elevate intracellular cAMP, and thereby activate PKA, may have a widespread anti-inflammatory effect in ASM cells. Since ICAM-1 and GM-CSF are highly NF-B-dependent genes, we used an adenoviral-delivered NF-B-dependent luciferase reporter to examine the effects of forskolin and the β₂-adrenoceptor agonists on NF-B activation. There was no effect on luciferase activity measured in the presence of forskolin or β₂-adrenoceptor agonists. This finding is consistent with the observation that IL-1β-induced expression of IL-6, a known NF-B-dependent gene in ASM, was also unaffected by β₂-adrenoceptor agonists, forskolin, PGE₂, 8-bromo-cAMP, or rolipram. Collectively, these results indicate that repression of IL-1β-induced ICAM-1 expression and GM-CSF release by cAMP-elevating agents, including β₂-adrenoceptor agonists, may not occur through a generic effect on NF-B.

human airway smooth muscle cells; asthma; inflammation; prostaglandin