Chemotaxis and calcium responses of phagocytes to formyl peptide receptor ligands is differentially regulated by cyclic ADP ribose
Chemotaxis and calcium responses of phagocytes to formyl peptide receptor ligands is differentially regulated by cyclic ADP ribose
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DOI：
10.4049/jimmunol.172.3.1896
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发表时间：
2004-02-01
影响因子：
4.4
通讯作者：
Lund, FE
中科院分区：
文献类型：
--
作者：
Partida-S치nchez, S;Iribarren, P;Lund, FE
环腺苷二磷酸核糖（cADPR）是一种钙动员代谢产物，调节细胞内钙释放和细胞外钙内流。虽然cADPR在调节钙动员中的作用已被广泛研究，但其在调节免疫应答中的潜在作用尚不清楚。我们以前报道过，cADPR，产生的ADP-核糖环化酶，CD 38，控制钙内流和趋化性的小鼠中性粒细胞响应fMLF，肽激动剂的两个趋化受体亚型，甲酰肽受体和甲酰肽受体样1。在这项研究中，我们研究是否需要cADPR的人单核细胞和中性粒细胞的趋化性，以各种各样的化学引诱物。我们发现，cADPR拮抗剂和CD 38底物类似物抑制人吞噬细胞的趋化性的甲酰基肽受体样1-特异性配体的数量，但没有影响这些细胞的趋化反应的甲酰基肽受体的选择性配体。此外，我们发现cADPR拮抗剂阻断人单核细胞对CXCR 4、CCR 1和CCR 5配体的趋化性。在所有情况下，我们发现cADPR调节由趋化因子激活的细胞中的细胞内游离钙水平，所述趋化因子在明显缺乏显著的细胞内钙释放的情况下诱导细胞外钙流入。因此，cADPR调节由人白细胞表达的化学引诱物受体的离散子集的钙信号传导。由于许多由cADPR调节的化学引诱物受体与临床病理学相关的配体结合，cADPR和CD 38代表了在慢性炎症和神经退行性疾病中具有潜在应用的新型药物靶点。
Cyclic ADP ribose (cADPR) is a calcium-mobilizing metabolite that regulates intracellular calcium release and extracellular calcium influx. Although the role of cADPR in modulating calcium mobilization has been extensively examined, its potential role in regulating immunologic responses is less well understood. We previously reported that cADPR, produced by the ADP-ribosyl cyclase, CD38, controls calcium influx and chemotaxis of murine neutrophils responding to fMLF, a peptide agonist for two chemoattractant receptor subtypes, formyl peptide receptor and formyl peptide receptor-like 1. In this study, we examine whether cADPR is required for chemotaxis of human monocytes and neutrophils to a diverse array of chemoattractants. We found that a cADPR antagonist and a CD38 substrate analogue inhibited the chemotaxis of human phagocytic cells to a number of formyl peptide receptor-like 1-specific ligands but had no effect on the chemotactic response of these cells to ligands selective for formyl peptide receptor. In addition, we show that the cADPR antagonist blocks the chemotaxis of human monocytes to CXCR4, CCR1, and CCR5 ligands. In all cases, we found that cADPR modulates intracellular free calcium levels in cells activated by chemokines that induce extracellular calcium influx in the apparent absence of significant intracellular calcium release. Thus, cADPR regulates calcium signaling of a discrete subset of chemoattractant receptors expressed by human leukocytes. Since many of the chemoattractant receptors regulated by cADPR bind to ligands that are associated with clinical pathology, cADPR and CD38 represent novel drug targets with potential application in chronic inflammatory and neurodegenerative disease.