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.