Effects of intracellular cyclic AMP modulators on human eosinophil survival, degranulation and CD11b expression.
BACKGROUND
Brochial asthma is characterized by infiltration of inflammatory cells such as lymphocytes and eosinophils. Theophylline is one of the most widely used drugs in the therapy of bronchial asthma, and phosphodiesterase (PDE) inhibition is thought to be an important mechanism of its anti-inflammatory actions. However, the detailed effects of PDE inhibition on eosinophils still remain unclear.


METHODS
Eosinophils in peripheral blood obtained from normal subjects and patients with mild off-season allergic rhinitis were purified using CD16 negative selection. The following effects of theophylline (nonselective PDE inhibitor), KF19514 (selective PDE IV inhibitor), mirlinone (selective PDE III inhibitor), procaterol (beta2-adrenoceptor agonist) and N6, 2'-O-dibutyryladenosine 3'5'-cyclic monophosphate (dB-cAMP; AMP analogue) on eosinophils were examined: (1) survival in the presence of interleukin-5, (2) degranulation by granulocyte/macrophage colony-stimulating factor (GM-CSF) or platelet-activating factor (PAF), (3) CD11b expression under GM-CSF or PAF stimulation and (4) intracellular cAMP level.


RESULTS
Eosinophil survival was inhibited by theophilline, KF19514 or procaterol. GM-CSF- or PAF-induced degranulation was inhibited by theophylline, KF19514, procaterol or dB-cAMP. CD11b up-regulation by PAF was inhibited by theophylline, KF19514 or dB-cAMP, while GM-CSF-stimulated CD11b up-regulation was not significantly inhibited by any of the drugs tested. The levels of intracellular cAMP were increased by theophylline, KF19514 and procaterol.


CONCLUSIONS
Intracellular cAMP is an important factor in the regulation of eosinophil biological functions. PDE IV inhibitors and beta2-agonists are suggested to be useful for the treatment of bronchial asthma through inhibition of eosinophil effector function.
First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
T
T
Momose
Y
Y
Okubo
S
S
Horie
J
J
Suzuki
M
M
Isobe
M
M
Sekiguchi
D003994:Bucladesine / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology*; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D016177:Macrophage-1 Antigen / Q000096:biosynthesis*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D017265:Procaterol / Q000494:pharmacology*; D012221:Rhinitis, Allergic, Perennial / Q000276:immunology
D016177:Macrophage-1 Antigen; D010726:Phosphodiesterase Inhibitors; D010972:Platelet Activating Factor; D003994:Bucladesine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000242:Cyclic AMP; D017265:Procaterol