Phosphodiesterase inhibitors suppress proliferation of peripheral blood mononuclear cells and interleukin-4 and -5 secretion by human T-helper type 2 cells.
It has been suggested that interleukin-4 and -5 (IL-4 and IL-5) are instrumental in the control of allergic disease. Elevated levels of IL-4 messenger RNA (mRNA) have been detected in numerous foci of atopic activity, including bronchoalveolar lavage (BAL) fluid from atopic asthmatics and skin of atopic dermatitis patients. IL-5 is important in eosinophil activation, which is a common feature of atopic disease. IL-5 mRNA has been detected in BAL fluid from both atopic and non-atopic asthmatics, indicating that IL-5 may be a common feature of the two disease states. Production of IL-4 and IL-5 by T cells appears to be associated with a high affinity cyclic AMP (cAMP) phosphodiesterase (PDE). This study was designed to compare the effects of PDE inhibitors Ro20-1724 and theophylline on (1) the mitogenic response of peripheral blood mononuclear cells from atopic and non-atopic individuals and (2) secretion of IL-4 and IL-5 by TH(2) cells after activation with PMA and anti-CD3. Both Ro20-1724 and theophylline inhibited proliferation of PBMC in a dose-dependent manner. There was no significant difference between proliferation of PBMC from atopic versus non-atopic donors, but Ro20-1724, a specific PDE IV inhibitor, was more potent at a concentration of 10(-5)M than theophylline in suppressing lymphocyte proliferation. Similarly, both PDE inhibitors suppressed secretion of IL-4 and IL-5 from TH(2)-like cell lines in a dose-dependent manner. In conclusion, as Ro20-1724 and theophylline inhibit proliferation of PBMC and secretion of IL-4 and IL-5 from human TH(2) cell lines, the development of a selective cyclic nucleotide PDE IV inhibitor may provide a promising new approach for asthma prophylaxis.
Crocker
I C
IC
Department of Pharmaceutical Sciences, Creighton University Health Sciences Center, Omaha, Nebraska 68178, USA.
Townley
R G
RG
Khan
M M
MM
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology
D006131:Growth Inhibitors; D015848:Interleukin-5; D010726:Phosphodiesterase Inhibitors; D015847:Interleukin-4; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D013806:Theophylline