Nd. Khoa et al., Inflammatory cytokines regulate function and expression of adenosine A(2A)receptors in human monocytic THP-1 cells, J IMMUNOL, 167(7), 2001, pp. 4026-4032
Adenosine, acting at its receptors, particularly A(2A) receptors, is a pote
nt endogenous anti-inflammatory agent that modulates the functions and diff
erentiation of inflammatory and immune cells. Because the inflammatory mili
eu abounds in proinflammatory cytokines, we investigated the effects of Th1
-inflammatory cytokines on function and expression of adenosine A(2A) recep
tors 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 A(2A) receptor agoni
st, suppress IL-12 production but increase IL-10 production in LPS-activate
d THP-1 cells. These effects were blocked by the A(2A) receptor antagonist
4-{2-[7-amino- 2-(2-fury')[1,2,4-triazolo[2,3-a][1,3,5]triazin-5-ylamino]et
hyl}phenol (ZM-241385). More importantly, the suppressive effect of adenosi
ne and CGS-21680 on IL-12 production was significantly enhanced in cells pr
etreated with either IL-1 (10 U/ml) or TNF-alpha (100 U/ml) but markedly at
tenuated in cells pretreated with IFN-gamma (100 U/ml). Similarly, IL-1 and
TNF-alpha treatment potentiated the stimulatory effect of adenosine and CG
S-21680 on IL-10 production, whereas IFN-gamma treatment almost completely
abolished this effect. CGS-21680 stimulated an increase in intracellular cA
MP in a time- and dose-dependent manner in IL-1- and TNF-alpha -treated cel
ls but not in control or IFN-gamma -treated cells. Both IL-1 and TNF-alpha
increased A(2A) receptor mRNA and protein. In parallel with its effect on A
(2A) receptor function, IFN-gamma down-regulated A(2A) receptor message and
protein. Because adenosine mediates many of the antiinflammatory effects o
f drugs such as methotrexate, these observations suggest that local changes
in the cytokine milieu may influence the therapeutic response to those dru
gs by altering the expression and function of adenosine receptors on inflam
matory cells.