Institute of Interdisciplinary Research, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 808 Route de Lennik, Brussels, Belgium.
Blood. 2010 Oct 28;116(17):3219-26. doi: 10.1182/blood-2010-01-265611. Epub 2010 Jul 22.
ATP, which has an important proinflammatory action as danger signal, induces the semimaturation of dendritic cells (DCs) that can be associated with immune tolerance. We identified epidermal growth factor receptor ligands as target genes of ATPγS, a slowly hydrolyzed ATP derivative, by a gene profiling approach in DCs. Amphiregulin was the most highly up-regulated gene in response to ATPγS. Human monocyte-derived DCs and mouse bone marrow-derived DCs released amphiregulin (AREG) after purinergic receptor activation, with a contribution of P2Y(11) and A(2B) receptor, respectively. Supernatants of LPS+ATPγS-stimulated DCs induced smooth muscle cell and Lewis Lung Carcinoma (LLC) cell growth in vitro. The coinjection of LPS+ATPγS-stimulated DCs or their supernatants with LLC cells increased tumor weight in mice compared with LPS-treated DCs. The preincubation of LPS+ATPγS-treated DC supernatants with an anti-AREG blocking antibody inhibited their positive effect on smooth muscle cell density and tumor growth. The present study demonstrates for the first time that DCs can be a source of AREG. ATP released from tumor cells might exert a tumorigenic action by stimulating the secretion of AREG from DCs. Antagonists of purinergic receptors expressed on DCs and anti-AREG blocking antibodies could have a therapeutic potential as antitumor agents.
三磷酸腺苷（ATP）作为危险信号具有重要的促炎作用，可诱导树突状细胞（DC）的半成熟，这可能与免疫耐受有关。我们通过基因谱分析方法在 DC 中鉴定出表皮生长因子受体配体是 ATPγS（一种缓慢水解的 ATP 衍生物）的靶基因。在 ATPγS 作用下，表皮生长因子受体配体中 Amphiregulin（AREG）基因的表达上调最为显著。人单核细胞来源的 DC 和小鼠骨髓来源的 DC 在嘌呤能受体激活后释放 Amphiregulin（AREG），分别由 P2Y（11）和 A（2B）受体贡献。LPS+ATPγS 刺激的 DC 上清液可诱导平滑肌细胞和 Lewis 肺癌细胞（LLC）体外生长。与 LPS 处理的 DC 相比，LPS+ATPγS 刺激的 DC 或其上清液与 LLC 细胞共注射可增加小鼠肿瘤重量。用抗 AREG 阻断抗体预先孵育 LPS+ATPγS 处理的 DC 上清液可抑制其对平滑肌细胞密度和肿瘤生长的正向作用。本研究首次证明 DC 可以成为 AREG 的来源。肿瘤细胞释放的 ATP 可能通过刺激 DC 分泌 AREG 发挥致瘤作用。表达于 DC 上的嘌呤能受体拮抗剂和抗 AREG 阻断抗体可能具有作为抗肿瘤药物的治疗潜力。
