title: Anti-inflammatory role of the cAMP effectors Epac and PKA: implications in chronic obstructive pulmonary disease.
abstract: Cigarette smoke-induced release of pro-inflammatory cytokines including interleukin-8 (IL-8) from inflammatory as well as structural cells in the airways, including airway smooth muscle (ASM) cells, may contribute to the development of chronic obstructive pulmonary disease (COPD). Despite the wide use of pharmacological treatment aimed at increasing intracellular levels of the endogenous suppressor cyclic AMP (cAMP), little is known about its exact mechanism of action. We report here that next to the β(2)-agonist fenoterol, direct and specific activation of either exchange protein directly activated by cAMP (Epac) or protein kinase A (PKA) reduced cigarette smoke extract (CSE)-induced IL-8 mRNA expression and protein release by human ASM cells. CSE-induced IκBα-degradation and p65 nuclear translocation, processes that were primarily reversed by Epac activation. Further, CSE increased extracellular signal-regulated kinase (ERK) phosphorylation, which was selectively reduced by PKA activation. CSE decreased Epac1 expression, but did not affect Epac2 and PKA expression. Importantly, Epac1 expression was also reduced in lung tissue from COPD patients. In conclusion, Epac and PKA decrease CSE-induced IL-8 release by human ASM cells via inhibition of NF-κB and ERK, respectively, pointing at these cAMP effectors as potential targets for anti-inflammatory therapy in COPD. However, cigarette smoke exposure may reduce anti-inflammatory effects of cAMP elevating agents via down-regulation of Epac1.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. a.oldenburger@rug.nl
authors.forename: Anouk
authors.initials: A
authors.lastname: Oldenburger
authors.forename: Sara S
authors.initials: SS
authors.lastname: Roscioni
authors.forename: Esther
authors.initials: E
authors.lastname: Jansen
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
authors.forename: Harm
authors.initials: H
authors.lastname: Maarsingh
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001980:Bronchi / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005280:Fenoterol / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D020662:Guanine Nucleotide Exchange Factors; D020672:I-kappa B Proteins; D016209:Interleukin-8; C000606204:NFKBIA protein, human; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D005280:Fenoterol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases