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Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide.
Br J Pharmacol 2012; 165(6):1877-1890BJ

Abstract

BACKGROUND AND PURPOSE

Lung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF-α, from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS.

EXPERIMENTAL APPROACH

Lung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE(2), the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF-α, PGE(2) and 6-keto PGF(1α) were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates.

KEY RESULTS

Expression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration-dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF-α from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE(2) (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE(2) (10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE(2) and 6-keto PGF(1α) release from lung macrophages which was associated with an up-regulation of COX-2 mRNA.

CONCLUSIONS AND IMPLICATIONS

Roflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF-α in human lung macrophages.

Authors+Show Affiliations

Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceMedical Intensive Care Unit, Georges Pompidou European Hospital, Paris, FranceDepartment of Pneumology University Paris-Descartes, APHP, Georges Pompidou European Hospital, Paris, FranceDepartment of Thoracic Surgery, Foch Hospital, University Versailles Saint-Quentin, Suresnes, FranceThoracic Surgery, Val d'Or Clinic, Saint-Cloud, FranceDepartment of Biology, Nycomed, Konstanz, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21913898

Citation

Buenestado, A, et al. "Roflumilast Inhibits the Release of Chemokines and TNF-α From Human Lung Macrophages Stimulated With Lipopolysaccharide." British Journal of Pharmacology, vol. 165, no. 6, 2012, pp. 1877-1890.
Buenestado A, Grassin-Delyle S, Guitard F, et al. Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide. Br J Pharmacol. 2012;165(6):1877-1890.
Buenestado, A., Grassin-Delyle, S., Guitard, F., Naline, E., Faisy, C., Israël-Biet, D., ... Devillier, P. (2012). Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide. British Journal of Pharmacology, 165(6), pp. 1877-1890. doi:10.1111/j.1476-5381.2011.01667.x.
Buenestado A, et al. Roflumilast Inhibits the Release of Chemokines and TNF-α From Human Lung Macrophages Stimulated With Lipopolysaccharide. Br J Pharmacol. 2012;165(6):1877-1890. PubMed PMID: 21913898.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide. AU - Buenestado,A, AU - Grassin-Delyle,S, AU - Guitard,F, AU - Naline,E, AU - Faisy,C, AU - Israël-Biet,D, AU - Sage,E, AU - Bellamy,J F, AU - Tenor,H, AU - Devillier,P, PY - 2011/9/15/entrez PY - 2011/9/15/pubmed PY - 2012/7/10/medline SP - 1877 EP - 1890 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 165 IS - 6 N2 - BACKGROUND AND PURPOSE: Lung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF-α, from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS. EXPERIMENTAL APPROACH: Lung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE(2), the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF-α, PGE(2) and 6-keto PGF(1α) were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates. KEY RESULTS: Expression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration-dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF-α from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE(2) (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE(2) (10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE(2) and 6-keto PGF(1α) release from lung macrophages which was associated with an up-regulation of COX-2 mRNA. CONCLUSIONS AND IMPLICATIONS: Roflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF-α in human lung macrophages. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/21913898/Roflumilast_inhibits_the_release_of_chemokines_and_TNF_α_from_human_lung_macrophages_stimulated_with_lipopolysaccharide_ L2 - https://doi.org/10.1111/j.1476-5381.2011.01667.x DB - PRIME DP - Unbound Medicine ER -