Suppression of granulocyte/macrophage colony-stimulating factor release from human monocytes by cyclic AMP-elevating drugs: role of interleukin-10.
1. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine secreted by cells of the monocyte/macrophage lineage and has been implicated in the pathogenesis of bronchitis and asthma. 2. In the present study we have evaluated the effect of several cyclic AMP-elevating agents on lipopolysaccharide (LPS)-induced GM-CSF release from human monocytes and the extent to which the anti-inflammatory cytokine, interleukin (IL)-10, is involved. 3. LPS evoked a concentration-dependent generation of GM-CSF from human monocytes that was inhibited, at the mRNA and protein level, by 8-Br-cyclic AMP, cholera toxin, prostaglandin E2 (PGE2) and a number of structurally dissimilar phosphodiesterase (PDE) 4 inhibitors. 4. Pre-treatment of monocytes with a concentration of an anti-IL-10 monoclonal antibody that abolished the inhibitory action of a maximally effective concentration of exogenous human recombinant IL-10, significantly augmented LPS-induced GM-CSF generation. This effect was associated with a parallel upwards displacement of the concentration-response curves that described the inhibition of GM-CSF by PGE2, 8-Br-cyclic AMP and the PDE4 inhibitor, rolipram, without significantly changing the potency of any drug. Consequently, the maximum percentage inhibition of GM-CSF release was reduced. Further experiments established that the reduction in the maximum inhibition of GM-CSF release seen in anti-IL-10-treated cells was not due to functional antagonism as rolipram, PGE2 and 8-Br-cyclic AMP were equi-effective at all concentrations of LPS studied. 5. These data indicate that cyclic AMP-elevating drugs attenuate the elaboration of GM-CSF from LPS-stimulated human monocytes by a mechanism that is not mediated via IL-10. Suppression of GM-CSF from monocytes may explain, at least in part, the efficacy of PDE4 inhibitors in clinical trials of chronic obstructive pulmonary disease.
Seldon
P M
PM
Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London SW3 6LY, UK.
Giembycz
M A
MA
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000494:pharmacology / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D000906:Antibodies; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D014970:Xanthines; C043898:denbufylline; D016753:Interleukin-10; D015124:8-Bromo Cyclic Adenosine Monophosphate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002772:Cholera Toxin; D000242:Cyclic AMP; D020889:Rolipram; D015232:Dinoprostone; D000420:Albuterol