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).

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) alpha 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)-1beta, 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 TNFalpha 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-1beta, IL-18, and CCL5, which are all known to be involved in the pathogenesis of COPD.

• Authors: Lauren M Kent, Lucy J C Smyth, Jonathan Plumb, Chris L Clayton, Steve M Fox, David W Ray, Stuart N Farrow, Dave Singh
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 328 Issue 2 Pg. 458-68 (Feb 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19004925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Guanidines
• Lipopolysaccharides
• 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
• Protein Kinase Inhibitors
• Pyrimidinones
• Dexamethasone
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Cell Culture Techniques
• Chemokines (metabolism)
• Dexamethasone (therapeutic use)
• Drug Interactions
• Gene Expression (drug effects)
• Guanidines (therapeutic use)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Lipopolysaccharides (toxicity)
• Macrophages (drug effects, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Pulmonary Disease, Chronic Obstructive (chemically induced, metabolism, prevention & control)
• Pyrimidinones (therapeutic use)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)