title: Differential expression of PDE4 cAMP phosphodiesterase isoforms in inflammatory cells of smokers with COPD, smokers without COPD, and nonsmokers.
abstract: The expression profile of a panel of 15 cAMP phosphodiesterase isoforms was determined for inflammatory cell types of relevance to chronic obstructive pulmonary disease (COPD). In particular, the expression profiles for bronchoalveolar macrophages, peripheral blood monocytes, T lymphocytes, and neutrophils from smokers with and without COPD were compared. The phosphodiesterase expression profile was also analyzed for peripheral blood monocytes, T lymphocytes, and neutrophils from nonsmokers and compared with smokers. Qualitative RT-PCR identified transcripts for PDE4A10, PDE4A7, PDE4B1, PDE4B2, PDE4D1, and PDE4D2 isoforms as well as transcripts for both PDE3B and PDE7A in T cells, monocytes, and macrophages in all subjects. Transcripts for PDE4B3 and PDE4D4 were not observed in any of the cell types investigated. PDE4C was detected in all cells analyzed except for T cells. The long PDE4A4, PDE4D3, and PDE4D5 isoforms exhibited cell type-specific expression patterns. Semiquantitative and real-time quantitative RT-PCR were used to analyze differential expression between disease states and between cell types. PDE4A4 was found significantly upregulated in lung macrophages from smokers with COPD when compared with control smokers. Furthermore, PDE4A4 as well as PDE4B2 transcripts were detected in higher amounts in peripheral blood monocytes of smokers when compared with nonsmokers. Finally, PDE4D5 and PDE4C were differentially regulated in lung macrophages when compared with monocytes of the same subjects, irrespective of the disease state. The data obtained suggest that PDE4A4 may be relevant as a macrophage-specific anti-inflammatory target for COPD.
authors.affiliation: Respiratory Disease Area, Novartis Horsham Research Center, Wimblehurst Road, Horsham RH12 5AB, United Kingdom.
authors.forename: Rachael
authors.initials: R
authors.lastname: Barber
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bergmann
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Shepherd
authors.forename: Ruth
authors.initials: R
authors.lastname: Sepper
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Gino Van
authors.initials: GV
authors.lastname: Heeke
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D017398:Alternative Splicing; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D009000:Monocytes / Q000201:enzymology; D009504:Neutrophils / Q000201:enzymology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects*; D013601:T-Lymphocytes / Q000201:enzymology
chemical_list: D007527:Isoenzymes; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human; C517361:PDE4C protein, human