Phosphodiesterase and cyclic adenosine monophosphate-dependent inhibition of T-lymphocyte chemotaxis

There is abundant evidence for T-lymphocyte recruitment into the airways in allergic inflammatory responses, This study has tested the hypothesis that T-cell chemotaxis induced by platelet-activating factor (PAF) and human re combinant interleukin-8 (hrIL-8) can be attenuated by inhibition of phospho diesterase activity and raised intracellular 3',5'-cyclic adenosine monopho sphate (cAMP) levels. This study used theophylline, a nonselective phosphodiesterase (PDE) inhibi tor, and rolipram, a selective PDE4 inhibitor, to study the effect of PDE i nhibition on T-cell chemotaxis. The beta(2)-adrenoceptor agonist, salbutamo l, the adenylyl cyclase activator, forskolin, and the cAMP analogue, dibuty ryl cAMP (db-cAMP), were used to demonstrate a role for raised cAMP levels. T-cells were obtained from 10 atopic asthmatics, and the phenotype of migr ating cells was examined by flow cytometry. Theophylline caused an inhibition of bath PAF-and hrIL-8-induced chemotaxis (mean+/-SEM maximum inhibition at 1 mM: 73+/-4% and 48+/-8% for hrIL-8 and PAF, respectively) that was not specific for the CD4+, CD8+, CD45RO+ or CD 45RA+ T-cell subsets. T-cell chemotaxis was more sensitive to treatment wit h rolipram whose effect was already significant from 0.1 mu M on hrIL-8-ind uced chemotaxis. Both a low concentration of salbutamol (0.1 mM) and forsko lin (10 mu M) potentiated the inhibitory effect of a low concentration of t heophylline (25 mu M) on responses to PAF but not to hrIL-8. Finally, T-cel l chemotaxis was also inhibited by db-cAMP. It is concluded that attenuation of T-cell chemotaxis to two chemoattractan ts of relevance to asthma pathogenesis can be achieved via phosphodiesteras e inhibition and increased intracellular 3', 5'-cyclic monophosphate using drugs active on cyclic nucleotide phosphodiesterase. This action may explai n the anti-inflammatory effects of theophylline and related drugs in asthma .