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Divisions of Clinical Pharmacology and Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016
Adenosine, acting at its receptors, particularly A2A
receptors, is a potent endogenous anti-inflammatory agent that
modulates the functions and differentiation of inflammatory and immune
cells. Because the inflammatory milieu abounds in proinflammatory
cytokines, we investigated the effects of Th1-inflammatory cytokines on
function and expression of adenosine A2A receptors in the
human monocytic cell line THP-1. We found that, consistent with
previous reports, adenosine and
2-[p-(2-carnonylethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine
(CGS-21680), a selective A2A receptor agonist, suppress
IL-12 production but increase IL-10 production in LPS-activated THP-1
cells. These effects were blocked by the A2A receptor
antagonist
4-{2-[7-amino-2-(2-furyl)[1,2,4-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol
(ZM-241385). More importantly, the suppressive effect of adenosine and
CGS-21680 on IL-12 production was significantly enhanced in cells
pretreated with either IL-1 (10 U/ml) or TNF-
(100 U/ml) but
markedly attenuated in cells pretreated with IFN-
(100 U/ml).
Similarly, IL-1 and TNF- treatment potentiated the stimulatory
effect of adenosine and CGS-21680 on IL-10 production, whereas IFN-
treatment almost completely abolished this effect. CGS-21680 stimulated
an increase in intracellular cAMP in a time- and dose-dependent manner
in IL-1- and TNF--treated cells but not in control or
IFN--treated cells. Both IL-1 and TNF- increased A2A
receptor mRNA and protein. In parallel with its effect on
A2A receptor function, IFN- down-regulated
A2A receptor message and protein. Because adenosine
mediates many of the antiinflammatory effects of drugs such as
methotrexate, these observations suggest that local changes in the
cytokine milieu may influence the therapeutic response to those drugs
by altering the expression and function of adenosine receptors on
inflammatory cells.
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