Received for publication July 9, 2008.
Revised September 23, 2008.
Accepted for publication October 21, 2008.

Inhibition of LPS Stimulated COPD Macrophage Inflammatory Gene Expression by Dexamethasone and the p38 MAPK Inhibitor SB706504

Abstract

p38 MAPK signalling is known to be increased in COPD macrophages. We have studied the effects of the p38 MAPK inhibitor SB706504 and dexamethasone on COPD macrophage inflammatory gene expression, and protein secretion. We also studied the effects of combined SB706504 and dexamethasone treatment. LPS stimulated monocyte derived macrophages (MDMs) and alveolar macrophages (AM) were cultured with dexamethasone and /or SB706504. MDMs were used for gene array and protein studies, while TNF protein production was measured from AM. 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 to SB706504 alone (-2.04) or dexamethasone (-3.39). 23 genes were insensitive to the effects of both drugs, including IL-1, IL-18 and CCL5. Also, the chromosome 4 chemokine cluster comprising CXCL1, CXCL2, CXCL3 and CXCL8 were all GC resistant. SB706504 significantly inhibited LPS stimulated TNF production from COPD and smoker AM, 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-1, IL-18 and CCL5, which are all known to be involved in the pathogenesis of COPD.

Key words: COPD, Dexamethasone, Macrophages, Microarray, SB706504, p38 MAPK