Am. J. Respir. Cell Mol. Biol., Vol 10, No. 5, May 1994, 565-572.
Theophylline suppresses human alveolar macrophage respiratory burst through phosphodiesterase inhibition
G Dent, MA Giembycz, KF Rabe, B Wolf, PJ Barnes and H Magnussen
Krankenhaus Grosshansdorf, LVA Hamburg, Germany.
The effects of theophylline upon human alveolar macrophage function were
assessed and compared with its action upon macrophage cyclic nucleotide
phosphodiesterase (PDE) activity and cyclic adenosine monophosphate (cAMP)
levels. In the concentration range of 10 mumol/liter to 1 mmol/liter,
theophylline caused a concentration- dependent inhibition of opsonized
zymosan-stimulated hydrogen peroxide (H2O2) generation and PDE-catalyzed
cAMP hydrolysis and increased the cellular cAMP content. Macrophage H2O2
generation was also inhibited by forskolin, an activator of adenylyl
cyclase, but whereas theophylline (1 mmol/liter) and forskolin (1
mumol/liter) exhibited a synergic elevation of macrophage cAMP, there was
no synergy between the two agents in the inhibition of respiratory burst.
The inhibition of H2O2 generation by theophylline was reversed by the
competitive inhibitor of cAMP-dependent protein kinase,
(Rp)8-bromoadenosine cyclic 3':5'- monophosphorothioate (Rp-8-Br-cAMPS; 100
mumol/liter), indicating that the functional effect of theophylline was
mediated through the elevation of cAMP. The inhibition of H2O2 generation
by theophylline was not affected by adenosine deaminase (0.1 U/ml),
indicating that the inhibition did not involve adenosine antagonism. It is
concluded that theophylline exerts a direct inhibitory action upon human
alveolar macrophage function through the elevation of cAMP levels as a
result of PDE inhibition, and that this effect is observed at
concentrations of theophylline that may be achieved in serum during
therapy.
