New insights in the bronchodilatory and anti-inflammatory mechanisms of action of theophylline.
Phosphodiesterase (PDE) inhibition and adenosine antagonism have been identified as important underlying mechanisms for the bronchodilating and anti-inflammatory action of theophylline (CAS 58-55-9). The aim of the present study was to determine the effects of PDE inhibition by theophylline on cAMP and arachidonic acid (AA) metabolism, namely leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) production, in cultured monocytes in vitro. Monocytes obtained from healthy non-smoking subjects were incubated in adherence at 37 degrees C for 4 h in the presence of theophylline (0.18, 1.8 and 18 micrograms/ml, respectively) and stimulated with LPS (10 micrograms/ml). LTB4, PGE2 and cAMP were measured in the same culture supernatants by direct enzyme immunoassay. LPS-stimulated generation of cAMP increased significantly (+162%) in the presence of theophylline (18 micrograms/ml); production of LTB4 was suppressed (-42%) compared to the baseline, whereas PGE2 production increased significantly (+39%). Production of cAMP correlated with increased PGE2 production (r = 0.73, p = 0.025) and with suppression of LTB4 (r = 0.67, p = 0.016). These effects were mimicked by cell permeant nucleotides, such as dibutyryl-cAMP but not by dibutyryl-cGMP and could be abolished by ibuprofen. These results provide the first evidence that the clinical efficacy of theophylline may result from inhibition of leukotriene production and its capacity to stimulate PGE2 production. The underlying mechanism is suggested as feedback regulatory induction of COX-2 by a prostaglandin driven cAMP-mediated process.
Juergens
U R
UR
Department of Pulmonary Diseases, Medical Policlinic, University Hospital, Bonn, Germany.
Degenhardt
V
V
Stöber
M
M
Vetter
H
H
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D013268:Stimulation, Chemical; D013806:Theophylline / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001993:Bronchodilator Agents; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D007975:Leukotriene B4; D013806:Theophylline; D000242:Cyclic AMP; D015232:Dinoprostone; D007052:Ibuprofen