| Abstrakt: |
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.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.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.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, PGE2and 8‐Br‐cyclic AMP were equi‐effective at all concentrations of LPS studied.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 viaIL‐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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