Khoa N D, Montesinos M C, Reiss A B, Delano D, Awadallah N, Cronstein B N
Division of Clinical Pharmacology, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
J Immunol. 2001 Oct 1;167(7):4026-32. doi: 10.4049/jimmunol.167.7.4026.
Adenosine, acting at its receptors, particularly A(2A) 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 A(2A) 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 A(2A) receptor agonist, suppress IL-12 production but increase IL-10 production in LPS-activated THP-1 cells. These effects were blocked by the A(2A) 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-alpha (100 U/ml) but markedly attenuated in cells pretreated with IFN-gamma (100 U/ml). Similarly, IL-1 and TNF-alpha treatment potentiated the stimulatory effect of adenosine and CGS-21680 on IL-10 production, whereas IFN-gamma 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-alpha-treated cells 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 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.
腺苷作用于其受体，尤其是A(2A)受体，是一种强效内源性抗炎剂，可调节炎症和免疫细胞的功能及分化。由于炎症环境中富含促炎细胞因子，我们研究了Th1炎性细胞因子对人单核细胞系THP-1中腺苷A(2A)受体功能和表达的影响。我们发现，与先前报道一致，腺苷和2-[对-(2-羰基乙基)苯乙氨基]-5'-N-乙基甲酰胺基腺苷（CGS-21680），一种选择性A(2A)受体激动剂，可抑制LPS激活的THP-1细胞中IL-12的产生，但增加IL-10的产生。这些作用被A(2A)受体拮抗剂4-(2-[7-氨基-2-(2-呋喃基)[1,2,4-三唑并[2,3-a][1,3,5]三嗪-5-基氨基]乙基)苯酚（ZM-241385）阻断。更重要的是，腺苷和CGS-21680对IL-12产生的抑制作用在用IL-1（10 U/ml）或TNF-α（100 U/ml）预处理的细胞中显著增强，但在用IFN-γ（100 U/ml）预处理的细胞中明显减弱。同样，IL-1和TNF-α处理增强了腺苷和CGS-21680对IL-10产生的刺激作用，而IFN-γ处理几乎完全消除了这种作用。CGS-21680在IL-1和TNF-α处理的细胞中以时间和剂量依赖的方式刺激细胞内cAMP增加，但在对照或IFN-γ处理的细胞中则无此作用。IL-1和TNF-α均增加A(2A)受体mRNA和蛋白水平。与对A(2A)受体功能的影响一致，IFN-γ下调A(2A)受体的信息和蛋白水平。由于腺苷介导了诸如甲氨蝶呤等药物的许多抗炎作用，这些观察结果表明细胞因子环境的局部变化可能通过改变炎症细胞上腺苷受体的表达和功能来影响对这些药物的治疗反应。
