Theophylline Represses IL-8 Secretion From ASM Cells Independently of PDE Inhibition: Novel Role as a PP2A Activator.

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Journal Article
American journal of respiratory cell and molecular biology, 2016, 54 (6), pp. 792 - 801
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Theophylline is an old drug experiencing a renaissance due to its beneficial anti-inflammatory effects in chronic respiratory diseases, such as asthma and COPD. Multiple modes of anti-inflammatory action have been reported, including inhibition of the enzymes that degrade cAMP - phosphodiesterase (PDE). Utilizing primary cultures of airway smooth muscle (ASM) cells, we recently revealed that PDE4 inhibitors can potentiate the anti-inflammatory action of β2-agonists by augmenting cAMP-dependent expression of the phosphatase that deactivates MAPK - 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 mRNA expression nor protein upregulation; consistent with the lack of cAMP generation. However, theophylline (at 10 µM) was anti-inflammatory and repressed secretion of the neutrophil chemoattractant cytokine, IL-8, produced in response to tumor necrosis factor α (TNFα). Because theophylline's effects were independent of PDE4 inhibition or anti-inflammatory MKP-1, we then wished to elucidate novel mechanisms responsible. We investigated the impact of theophylline on protein phosphatase 2A (PP2A), a master controller of multiple inflammatory signaling pathways, and show that theophylline increases TNFα-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.
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