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Research ArticleCELLULAR AND MOLECULAR

Inhibition of Lipopolysaccharide-Stimulated Chronic Obstructive Pulmonary Disease Macrophage Inflammatory Gene Expression by Dexamethasone and the p38 Mitogen-Activated Protein Kinase Inhibitor N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-2-yl]amino}ethyl)guanidine (SB706504)

Lauren M. Kent, Lucy J. C. Smyth, Jonathan Plumb, Chris L. Clayton, Steve M. Fox, David W. Ray, Stuart N. Farrow and Dave Singh
Journal of Pharmacology and Experimental Therapeutics February 2009, 328 (2) 458-468; DOI: https://doi.org/10.1124/jpet.108.142950
Lauren M. Kent
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Lucy J. C. Smyth
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Jonathan Plumb
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Chris L. Clayton
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Steve M. Fox
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David W. Ray
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Stuart N. Farrow
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Dave Singh
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Abstract

p38 mitogen-activated protein kinase (MAPK) signaling is known to be increased in chronic obstructive pulmonary disease (COPD) macrophages. We have studied the effects of the p38 MAPK inhibitor N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl]amino}ethyl)guanidine (SB706504) and dexamethasone on COPD macrophage inflammatory gene expression and protein secretion. We also studied the effects of combined SB706504 and dexamethasone treatment. Lipopolysaccharide (LPS)-stimulated monocyte derived macrophages (MDMs) and alveolar macrophages (AMs) were cultured with dexamethasone and/or SB706504. MDMs were used for gene array and protein studies, whereas tumor necrosis factor (TNF) α protein production was measured from AMs. SB706504 caused transcriptional inhibition of a range of cytokines and chemokines in COPD MDMs. The use of SB706504 combined with dexamethasone caused greater suppression of gene expression (-8.90) compared with SB706504 alone (-2.04) or dexamethasone (-3.39). Twenty-three genes were insensitive to the effects of both drugs, including interleukin (IL)-1β, IL-18, and chemokine (CC motif) ligand (CCL) 5. In addition, the chromosome 4 chemokine cluster members, CXCL1, CXCL2, CXCL3, and CXCL8, were all glucocorticoid-resistant. SB706504 significantly inhibited LPS-stimulated TNFα production from COPD and smoker AMs, with near-maximal suppression caused by combination treatment with dexamethasone. We conclude that SB706504 targets a subset of inflammatory macrophage genes and when used with dexamethasone causes effective suppression of these genes. SB706504 and dexamethasone had no effect on the transcription of a subset of LPS-regulated genes, including IL-1β, IL-18, and CCL5, which are all known to be involved in the pathogenesis of COPD.

Footnotes

  • This work was supported by the Biotechnology and Biological Sciences Research Council and GlaxoSmithKline [Grant BBS/S/N/2004/11516].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.142950.

  • ABBREVIATIONS: COPD, chronic obstructive pulmonary disease; AM, alveolar macrophage; GC, glucocorticoid; GR, glucocorticoid receptor; NF, nuclear factor; TLR, Toll-like receptor; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; TNF, tumor necrosis factor; IL, interleukin; GM-CSF, granulocyte macrophage colony-stimulating factor; MDM, monocyte-derived macrophage; PCR, polymerase chain reaction; UP, ultrapure; DMSO, dimethyl sulfoxide; qPCR, quantitative PCR; ELISA, enzyme-linked immunosorbent assay; IPA, ingenuity pathways analysis; FEV, forced expiratory volume; FVC, forced vital capacity; CCL, chemokine (CC motif) ligand; SB706504, N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine; SB239063, trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)imidazole; SD-282, indole-5-carboxamide (ATP-competitive inhibitor of p38 kinase).

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received July 9, 2008.
    • Accepted October 21, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Inhibition of Lipopolysaccharide-Stimulated Chronic Obstructive Pulmonary Disease Macrophage Inflammatory Gene Expression by Dexamethasone and the p38 Mitogen-Activated Protein Kinase Inhibitor N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylp…
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Research ArticleCELLULAR AND MOLECULAR

Inhibition of Lipopolysaccharide-Stimulated Chronic Obstructive Pulmonary Disease Macrophage Inflammatory Gene Expression by Dexamethasone and the p38 Mitogen-Activated Protein Kinase Inhibitor N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-2-yl]amino}ethyl)guanidine (SB706504)

Lauren M. Kent, Lucy J. C. Smyth, Jonathan Plumb, Chris L. Clayton, Steve M. Fox, David W. Ray, Stuart N. Farrow and Dave Singh
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 458-468; DOI: https://doi.org/10.1124/jpet.108.142950

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Research ArticleCELLULAR AND MOLECULAR

Inhibition of Lipopolysaccharide-Stimulated Chronic Obstructive Pulmonary Disease Macrophage Inflammatory Gene Expression by Dexamethasone and the p38 Mitogen-Activated Protein Kinase Inhibitor N-cyano-N′-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-2-yl]amino}ethyl)guanidine (SB706504)

Lauren M. Kent, Lucy J. C. Smyth, Jonathan Plumb, Chris L. Clayton, Steve M. Fox, David W. Ray, Stuart N. Farrow and Dave Singh
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 458-468; DOI: https://doi.org/10.1124/jpet.108.142950
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