PHOSPHODIESTERASE INHIBITORS SUPPRESS PROLIFERATION OF PERIPHERAL-BLOOD MONONUCLEAR-CELLS AND INTERLEUKIN-4 AND INTERLEUKIN-5 SECRETION BY HUMAN T-HELPER TYPE-2 CELLS

It has been suggested that interleukin-4 and -5 (IL-4 and IL-5) are in strumental in the control of allergic disease. Elevated levels of IL-4 messenger RNA (mRNA) have been detected in numerous foci of atopic ac tivity, including bronchoalveolar lavage (BAL) fluid from atopic asthm atics and skin of atopic dermatitis patients. IL-5 is important in eos inophil activation, which is a common feature of atopic disease. IL-5 mRNA has been detected in BAL fluid from both atopic and non-atopic as thmatics, indicating that IL-5 may be a common feature of the two dise ase states, Production of IL-4 and IL-5 by T cells appears to be assoc iated 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 bloo d mononuclear cells from atopic and non-atopic individuals and (2) sec retion of IL-4 and IL-5 by TH2 cells after activation with PMA and ant i-CD3. Both Ro20-1724 and theophylline inhibited proliferation of PBMC in a dose-dependent manner, There was no significant difference betwe en proliferation of PBMC from atopic versus non-atopic donors, but Ro2 0-1724, a specific PDE IV inhibitor, was more potent at a concentratio n of 10(-5)M than theophylline in suppressing lymphocyte proliferation . Similarly, both PDE inhibitors suppressed secretion of IL-4 and IL-5 from TH2-like cell lines in a dose-dependent manner. In conclusion, a s Ro20-1724 and theophylline inhibit proliferation of PBMC and secreti on of IL-4 and IL-5 from human TH2 cell lines, the development of a se lective cyclic nucleotide PDE IV inhibitor may provide a promising new approach for asthma prophylaxis.