Inflammatory cytokines regulate function and expression of adenosine A(2A)receptors in human monocytic THP-1 cells

Citation
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
Citations number
32
Categorie Soggetti
Immunology
Journal title
JOURNAL OF IMMUNOLOGY
ISSN journal
00221767 → ACNP
Volume
167
Issue
7
Year of publication
2001
Pages
4026 - 4032
Database
ISI
SICI code
0022-1767(20011001)167:7<4026:ICRFAE>2.0.ZU;2-F
Abstract
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.