title: Theophylline Represses IL-8 Secretion from Airway Smooth Muscle Cells Independently of Phosphodiesterase Inhibition. Novel Role as a Protein Phosphatase 2A Activator.
abstract: Theophylline is an old drug experiencing a renaissance owing to its beneficial antiinflammatory effects in chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Multiple modes of antiinflammatory action have been reported, including inhibition of the enzymes that degrade cAMP-phosphodiesterase (PDE). Using primary cultures of airway smooth muscle (ASM) cells, we recently revealed that PDE4 inhibitors can potentiate the antiinflammatory action of β2-agonists by augmenting cAMP-dependent expression of the phosphatase that deactivates mitogen-activated protein kinase (MAPK)-MAPK phosphatase (MKP)-1. Therefore, the aim of this study was to address whether theophylline repressed cytokine production in a similar, PDE-dependent, MKP-1-mediated manner. Notably, theophylline did not potentiate cAMP release from ASM cells treated with the long-acting β2-agonist formoterol. Moreover, theophylline (0.1-10 μM) did not increase formoterol-induced MKP-1 messenger RNA expression nor protein up-regulation, consistent with the lack of cAMP generation. However, theophylline (at 10 μM) was antiinflammatory and repressed secretion of the neutrophil chemoattractant cytokine IL-8, which is produced in response to TNF-α. Because theophylline's effects were independent of PDE4 inhibition or antiinflammatory MKP-1, we then wished to elucidate the novel mechanisms responsible. We investigated the impact of theophylline on protein phosphatase (PP) 2A, a master controller of multiple inflammatory signaling pathways, and show that theophylline increases TNF-α-induced PP2A activity in ASM cells. Confirmatory results were obtained in A549 lung epithelial cells. PP2A activators have beneficial effects in ex vivo and in vivo models of respiratory disease. Thus, our study is the first to link theophylline with PP2A activation as a novel mechanism to control respiratory inflammation.
authors.affiliation: 1 Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Brijeshkumar S
authors.initials: BS
authors.lastname: Patel
authors.affiliation: 1 Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Md Mostafizur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: 1 Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Nowshin N
authors.initials: NN
authors.lastname: Rumzhum
authors.affiliation: 2 Woolcock Institute of Medical Research, University of Sydney, New South Wales, Australia.|3 School of Life Sciences, University of Technology, Sydney, New South Wales, Australia; and.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Oliver
authors.affiliation: 4 School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, New South Wales.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Verrills
authors.affiliation: 1 Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D000072283:A549 Cells; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology*; D000068759:Formoterol Fumarate / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D020536:Enzyme Activators; D016209:Interleukin-8; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D013806:Theophylline; D000242:Cyclic AMP; D054648:Protein Phosphatase 2; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D000068759:Formoterol Fumarate
keywords: IL-8; airway smooth muscle; cAMP; phosphodiesterase; protein phosphatase 2A