Theophylline Inhibits TNF-α-Induced CD4 Expression on Human Eosinophils and CD4+ Eosinophil Migration

Abstract

Background: Increasing evidence regarding asthma suggests that CD4+ cells are preferentially recruited to sites of bronchial inflammation. Interleukin (IL)-16 has been reported as playing an important role in the accumulation of CD4+ cells. We have shown that the CD4 molecule is expressed on normal human eosinophils by tumor necrosis factor (TNF)-α stimulation. Methods: We evaluated the effects of theophylline, KF19514 [a selective phosphodiesterase (PDE) IV inhibitor] and dexamethasone on CD4 expression on eosinophils and eosinophil migration in response to IL-16, a natural soluble ligand of the CD4 molecule. Results: The maximum eosinophil migration was observed when eosinophils were cultured with TNF-α at 10 ng/ml for 18 h and the concentration of IL-16 was 10 pg/ml. CD4+ eosinophil migration in response to IL-16 was mostly, if not fully, chemokinetic and this migration was significantly inhibited by Fab of anti-CD4 monoclonal antibody. Theophylline (10^–4–10^–3M), KF19514 (10^–7–10^–6M) and dexamethasone (10^–8– 10^–6M) significantly inhibited CD4 expression on eosinophils induced by TNF-α. Theophylline (10^–3M) and KF19514 (10^–6M) inhibited CD4+ eosinophil migratory responses induced by IL-16, but 10^–6M dexamethasone did not. Theophylline and KF19514 augmented the intracellular adenosine-3′,5′-cyclic monophosphate (cAMP) concentration in eosinophils, suggesting modulation by cAMP of CD4 expression and eosinophil migration. Conclusions: These data suggest that TNF-α-induced CD4+ eosinophils may contribute to eosinophil migratory responses induced by IL-16. Theophylline and selective PDE IV inhibitor may prevent airway inflammation by downregulating CD4 expression on eosinophils and inhibiting eosinophil migration through CD4 and IL-16 interaction.