Haschemi Arvand, Wagner Oswald, Marculescu Rodrig, Wegiel Barbara, Robson Simon C, Gagliani Nicola, Gallo David, Chen Jiang-Fan, Bach Fritz H, Otterbein Leo E
Transplant and Immunobiology Research Centers, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA.
J Immunol. 2007 May 1;178(9):5921-9. doi: 10.4049/jimmunol.178.9.5921.
Adenosine and heme oxygenase-1 (HO-1) exert a wide range of anti-inflammatory and immunomodulatory actions, making them crucial regulatory molecules. Despite the diversity in their modes of action, the similarity of biological effects of adenosine and HO-1 led us to hypothesize a possible interrelationship between them. We assessed a potential role for HO-1 in the ability of adenosine or 5'-N-ethylcarboxamidoadenosine (NECA), a stable adenosine analog, to modify the response of LPS-stimulated macrophages. Adenosine and NECA markedly induced HO-1 and blocked LPS-induced TNF-alpha production via adenosine A2aR-mediated signaling; blocking of HO-1 by RNA interference abrogated the effects of adenosine and NECA on TNF-alpha. HO-1 overexpression or exposure to carbon monoxide (CO), a product of HO-1 enzymatic activity, resulted in augmented A2aR mRNA and protein levels in RAW264.7 cells and primary macrophages. The induction of A2aR expression by HO-1 or CO resulted in an increase in the sensitivity to the anti-inflammatory effects of adenosine and NECA, which was lost in macrophages isolated from A2aR-deficient mice. Moreover, a decrease in cAMP levels upon NECA stimulation of naive macrophages was counterbalanced by CO exposure to up-regulate A2aR levels. This implies adenosine receptor isoform switch as a selective modification in macrophage phenotype. Taken together, these data suggest the existence of a positive feedback loop among adenosine, HO-1, CO, and the A2aR in the chronological resolution of the inflammatory response.
腺苷和血红素加氧酶-1（HO-1）具有广泛的抗炎和免疫调节作用，使其成为关键的调节分子。尽管它们的作用方式存在差异，但腺苷和HO-1生物学效应的相似性使我们推测它们之间可能存在相互关系。我们评估了HO-1在腺苷或5'-N-乙基羧酰胺腺苷（NECA，一种稳定的腺苷类似物）调节脂多糖（LPS）刺激的巨噬细胞反应能力中的潜在作用。腺苷和NECA通过腺苷A2aR介导的信号通路显著诱导HO-1，并阻断LPS诱导的肿瘤坏死因子-α（TNF-α）产生；RNA干扰阻断HO-1可消除腺苷和NECA对TNF-α的影响。HO-1过表达或暴露于HO-1酶活性产物一氧化碳（CO）可导致RAW264.7细胞和原代巨噬细胞中A2aR mRNA和蛋白水平升高。HO-1或CO诱导A2aR表达导致对腺苷和NECA抗炎作用的敏感性增加，而在从A2aR缺陷小鼠分离的巨噬细胞中这种敏感性丧失。此外，NECA刺激未激活的巨噬细胞后cAMP水平的降低可通过CO暴露上调A2aR水平来抵消。这意味着腺苷受体亚型转换是巨噬细胞表型的一种选择性改变。综上所述，这些数据表明在炎症反应的时间性消退过程中，腺苷、HO-1、CO和A2aR之间存在正反馈回路。
