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-asthmatic drugs on the production of the CC chemokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha), in response to lipopolysaccharide (LPS) by peripheral blood mononuclear cells (PBMC). MIP-1 alpha production was induced by LPS in a concentration-dependent fashion and reached the maximum at 10 micrograms/ml LPS (27.5 +/- 2.3 ng MIP-1 alpha/10(6) PBMC). At a submaximal concentration of LPS (1 microgram/ml), the release of MIP-1 alpha increased with time and reached the maximum 24 h after LPS stimulation. Actinomycin D and cycloheximide inhibited MIP-1 alpha production completely, but glucocorticoids did not completely inhibit MIP-1 alpha production, with a maximum inhibition of 70%. We examined the effect of beta-stimulants and phosphodiesterase inhibitors, which upregulate intracellular cyclic AMP levels, on MIP-1 alpha production. When PBMC were treated with beta-stimulants alone, beta-stimulants showed a slightly inhibitory effect on MIP-1 alpha production. However, the coadministration of roliplam significantly potentiated the inhibitory effect of beta-stimulants on MIP-1 alpha production. Moreover, db-cAMP suppressed MIP-1 alpha production dose-dependently. The above data indicate that the production of MIP-1 alpha is regulated by cyclic AMP and that 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.
Kimata
M
M
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Shichijo
M
M
Daikoku
M
M
Inagaki
N
N
Mori
H
H
Nagai
H
H
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D054407:Chemokine CCL4; D004731:Endotoxins; D004926:Escherichia coli; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D054407:Chemokine CCL4; D004731:Endotoxins; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D010726:Phosphodiesterase Inhibitors; D011500:Protein Synthesis Inhibitors; D003994:Bucladesine; C044101:endotoxin, Escherichia coli