PHARMACOLOGICAL MODULATION OF LPS-INDUCED MIP-1-ALPHA PRODUCTION BY PERIPHERAL-BLOOD MONONUCLEAR-CELLS

In the present study, we investigated the effects of some anti-asthmat ic drugs on the production of the CC chemokine, macrophage inflammator y protein-1 alpha (MIP-1 alpha.), in response to lipopolysaccharide (L PS) by peripheral blood mononuclear cells (PBMC). MIP-1 alpha producti on was induced by LPS in a concentration-dependent fashion and reached the maximum at 10 mu g/ml LPS (27.5 +/- 2.3 ng MIP-1 alpha/10(6) PBMC ). At a submaximal concentration of LPS (1 mu g/ml), the release of MI P-1 alpha increased with time and reached the maximum 24 h after LPS s timulation. Actinomycin D and cycloheximide inhibited MIP-la productio n completely, but glucocorticoids did not completely inhibit MIP-1 alp ha production, with a maximum inhibition of 70%. We examined the effec t of beta-stimulants and phosphodiesterase inhibitors, which upregulat e intracellular cyclic AMP levels, on MIP-1 alpha production. When PBM C were treated with beta-stimulants alone, beta-stimulants showed a sl ightly inhibitory effect on MIP-1 alpha production. However, the coadm inistration of roliplam significantly potentiated the inhibitory effec t of beta-stimulants on MIP-1 alpha production. Moreover, db-cAMP supp ressed MIP-1 alpha production dose-dependently. The above data indicat e that the production of MIP-1 alpha is regulated by cyclic AMP and th at cyclic AMP could provide a useful target for therapeutic treatment in asthmatic diseases and other diseases where MIP-1 alpha is involved in their etiology.