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

被引:57
作者
Kaur, Manminder [1 ,2 ,3 ]
Holden, Neil S. [1 ]
Wilson, Sylvia M. [2 ]
Sukkar, Maria B. [4 ]
Chung, Kian Fan [3 ]
Barnes, Peter J. [3 ]
Newton, Robert [1 ]
Giembycz, Mark A. [2 ]
机构
[1] Univ Calgary, Fac Med, Dept Cell Biol & Anat, Calgary, AB T2N 4N1, Canada
[2] Univ Calgary, Fac Med, Airway Inflammat Grp, Dept Pharmacol & Therapeut, Calgary, AB T2N 4N1, Canada
[3] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Airway Dis Sect, London, England
[4] Univ Sydney, Fac Pharm, Resp Res Grp, Sydney, NSW 2006, Australia
基金
加拿大健康研究院; 英国医学研究理事会;
关键词
human airway smooth muscle cells; asthma; inflammation; prostaglandin;
D O I
10.1152/ajplung.00046.2008
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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) beta(2)-adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1 beta in ASM cells. IL-1 beta-induced IL-8 release was also repressed by PGE2 and forskolin, whereas the beta(2)-adrenoceptor agonists were ineffective. In each case, repression of these inflammatory indexes was prevented by adenoviral overexpression of PKI alpha, 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-kappa B-dependent genes, we used an adenoviral-delivered NF-kappa B-dependent luciferase reporter to examine the effects of forskolin and the beta(2)-adrenoceptor agonists on NF-kappa B activation. There was no effect on luciferase activity measured in the presence of forskolin or beta(2)-adrenoceptor agonists. This finding is consistent with the observation that IL-1 beta-induced expression of IL-6, a known NF-kappa B-dependent gene in ASM, was also unaffected by beta(2)-adrenoceptor agonists, forskolin, PGE2, 8-bromo-cAMP, or rolipram. Collectively, these results indicate that repression of IL-1 beta-induced ICAM-1 expression and GM-CSF release by cAMP-elevating agents, including beta(2)-adrenoceptor agonists, may not occur through a generic effect on NF-kappa B.
引用
收藏
页码:L505 / L514
页数:10
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