title: Cigarette smoke extract induced cytokine and chemokine gene expression changes in COPD macrophages.
abstract: Macrophages are key inflammatory cells in chronic obstructive pulmonary disease (COPD). The transcriptional regulation of inflammatory signalling pathways by cigarette smoke (CS) in COPD macrophages is not well understood. We have studied the effects of acute CS exposure on COPD macrophage cytokine, chemokine and signal transduction gene expression profiles. Monocyte derived macrophages (MDMs) from whole blood from patients with COPD (n=6) were stimulated with 1%, 10% and 25% CS extract (CSE) for 6h for microarray and quantitative polymerase chain reaction (Q-PCR) analysis. We observed a CSE dose dependant increase in the numbers of significantly regulated genes; 24, 340 and 627 genes at 1%, 10% and 25% CSE, respectively. IL-8 mRNA levels were up-regulated by 10% CSE (2.25-fold increase, 95% CI 1.28-4.00). In contrast a range of other cytokines and chemokines were down-regulated at both 10% and 25% CSE, including IL-1beta, -6, -10 and -18, chemokine ligands CCL-2, -3, -4, -5, -8, -15, -20 and CXCL-1, -2 and -10. Q-PCR and microarray data were highly correlated (r=0.95, p=0.0001). NF-kappaB component p50 and IkappaBalpha expression were suppressed by CSE, while there was up-regulation of the AP-1 components c-Jun, FOSL1 and FOSL2. Acute CSE exposure decreased macrophage inflammatory gene expression, with the exception of increased IL-8. There was diverse regulation of key inflammatory signal pathway genes. The effects of acute CS exposure appear to encompass both up-regulation of chemotaxis mechanisms through IL-8, but also down-regulation of innate immunity.
authors: Education and Research Centre, South Manchester University Hospitals Trust/University of Manchester, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. Electronic address: lauren_m_kent@yahoo.co.uk.
authors: Lauren
authors: L
authors: Kent
authors: Education and Research Centre, South Manchester University Hospitals Trust/University of Manchester, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. Electronic address: ljcsmyth@yahoo.co.uk.
authors: Lucy
authors: L
authors: Smyth
authors: Molecular Discovery Research, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: chris.l.clayton@gsk.com.
authors: Chris
authors: C
authors: Clayton
authors: Molecular Discovery Research, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: laurie.k.scott@gsk.com.
authors: Laurie
authors: L
authors: Scott
authors: Molecular Discovery Research, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: Ted.Cook@gsk.com.
authors: Ted
authors: T
authors: Cook
authors: Molecular Discovery Research, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: richard.j.stephens@gsk.com.
authors: Richard
authors: R
authors: Stephens
authors: Statistical Sciences, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: steven.m.fox@gsk.com.
authors: Steve
authors: S
authors: Fox
authors: Statistical Sciences, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: peter.p.hext@gsk.com.
authors: Peter
authors: P
authors: Hext
authors: Target Discovery, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: stuart.n.farrow@gsk.com.
authors: Stuart
authors: S
authors: Farrow
authors: Education and Research Centre, South Manchester University Hospitals Trust/University of Manchester, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. Electronic address: dsingh@meu.org.uk.
authors: Dave
authors: D
authors: Singh
mesh_terms: D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010936:Plant Extracts / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology; D012906:Smoke; D014026:Nicotiana
chemical_list: D018925:Chemokines; D016207:Cytokines; D010936:Plant Extracts; D012906:Smoke