Anti-inflammatory effects of thiazolidinediones in human airway smooth muscle cells
Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Tro...
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Published in | American journal of respiratory cell and molecular biology Vol. 45; no. 1; pp. 111 - 119 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Thoracic Society
01.07.2011
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Subjects | |
Online Access | Get full text |
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Summary: | Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dose-dependently reduced the IL-1β-induced release of IL-6 and vascular endothelial growth factor, the TNF-α-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-α-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-γ (PPARγ), these anti-inflammatory effects were not affected by a specific PPARγ inhibitor (GW 9662) or by the knockdown of PPARγ using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the anti-inflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARγ or AMPK. |
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Bibliography: | This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Author Disclosure: R.A.P. has served as a scientific consultant for Astra-Zeneca ($1,001–$5,000), Merck ($1,001–$5,000), and GlaxoSmithKline ($1,001–$5,000), has served on scientific advisory boards for BioMarck ($1,001–$5,000), Cytokinetics ($1,001–$5,000), and Epigenesis ($1,001–$5,000), has received lecture fees from Astra-Zeneca ($1,001–$5,000), and has received industry-sponsored grants from Immune Control ($10,001–$50,000), Astra-Zeneca ($10,001–$50,000), and the National Institutes of Health (more than $100,001). S.A.S. has served on an advisory board for Schering Plough ($1,001–$5,000), has received lecture fees from Merck Pharmaceutical Co. ($1,001–$5,000) and Merck Frost Canada (up to $1,000), and has received industry-sponsored grants from the National Institutes of Health (more than $100,001). None of the other authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. This study was supported by National Heart, Lung, and Blood Institute grants HL-084044 and HL097032, and by National Institute of Environmental Health Sciences grants ES-013307, ES-00002, and HL-084044 (S.A.S.). Originally Published in Press as DOI: 10.1165/rcmb.2009-04450C on September 24, 2010 |
ISSN: | 1044-1549 1535-4989 |
DOI: | 10.1165/rcmb.2009-0445OC |