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Saturday 01 September 2001

Suppression of granulocyte/macrophage colony-stimulating factor release from human monocytes by cyclic AMP-elevating drugs: role of interleukin-10.

By: Seldon PM, Giembycz MA.

Br J Pharmacol 2001 Sep;134(1):58-67

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.

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