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 recombinant interleukin-8 (hrIL-8) can be attenuated by inhibition of phosphodiesterase activity and raised intracellular 3',5'-cyclic adenosine monophosphate (cAMP) levels. This study used theophylline, a nonselective phosphodiesterase (PDE) inhibitor, and rolipram, a selective PDE4 inhibitor, to study the effect of PDE inhibition on T-cell chemotaxis. The beta2-adrenoceptor agonist, salbutamol, the adenylyl cyclase activator, forskolin, and the cAMP analogue, dibutyryl 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 migrating cells was examined by flow cytometry. Theophylline caused an inhibition of both 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 CD45RA+ T-cell subsets. T-cell chemotaxis was more sensitive to treatment with rolipram whose effect was already significant from 0.1 microM on hrIL-8-induced chemotaxis. Both a low concentration of salbutamol (0.1 mM) and forskolin (10 microM) potentiated the inhibitory effect of a low concentration of theophylline (25 microM) on responses to PAF but not to hrIL-8. Finally, T-cell chemotaxis was also inhibited by db-cAMP. It is concluded that attenuation of T-cell chemotaxis to two chemoattractants of relevance to asthma pathogenesis can be achieved via phosphodiesterase inhibition and increased intracellular 3', 5'-cyclic monophosphate using drugs active on cyclic nucleotide phosphodiesterase. This action may explain the anti-inflammatory effects of theophylline and related drugs in asthma.
Hidi
R
R
University Medicine, Southampton General Hospital, UK.
Timmermans
S
S
Liu
E
E
Schudt
C
C
Dent
G
G
Holgate
S T
ST
Djukanović
R
R
D000420:Albuterol / Q000494:pharmacology; D001249:Asthma / Q000276:immunology; D003994:Bucladesine / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013806:Theophylline / Q000494:pharmacology
D016209:Interleukin-8; D010726:Phosphodiesterase Inhibitors; D010972:Platelet Activating Factor; D005576:Colforsin; D003994:Bucladesine; D013806:Theophylline; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D020889:Rolipram; D000420:Albuterol