Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC
Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC
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DOI：
10.1074/jbc.272.23.14893
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发表时间：
1997-06-06
影响因子：
4.8
通讯作者：
Yoshie, O
中科院分区：
文献类型：
--
作者：
Baba, M;Imai, T;Yoshie, O
肝活化调节趋化因子（Liver and activation-regulated chemokine， LARC）是最近发现的一种主要在肝脏表达的CC趋化因子。LARC作为淋巴细胞的选择性趋化剂，表达一类高亲和力特异性结合LARC的受体。为了鉴定LARC的受体，我们在稳定表达5种CC趋化因子受体（CCR1-CCR5）和5种孤儿7跨膜受体的细胞中检测了LARC诱导的钙动员。LARC在稳定表达孤儿受体GPR-CY4的K562细胞和293/EBNA-1细胞中特异性诱导钙通量。LARC诱导表达GPR-CY4的293/EBNA-1细胞稳定迁移，呈双峰量效曲线。LARC与分泌性碱性磷酸酶（LARC- seap）融合，特异结合Raji细胞，稳定表达GPR-CY4， K-d为0.9 nM。只有LARC而不是其他五种CC趋化因子（MCP-1， RANTES, MIP-1 α， MIP-1 β和TARC）与LARC- seap结合GPR-CY4。Northern blot分析发现，GPR-CY4 mRNA在人体各组织中主要表达于脾脏、淋巴结、阑尾和胎儿肝脏。在各种白细胞亚群中，在淋巴细胞（CD4（+）和CD8(+) T细胞和B细胞）中检测到GPR-CY4 mRNA，但在自然杀伤细胞、单核细胞或粒细胞中未检测到。GPR-CY4 mRNA在CD4（+）和CD8(+) T细胞中的表达被IL-2强烈上调。综上所述，GPR-CY4是LARC在淋巴细胞上选择性表达的特异性受体，而LARC是GPR-CY4独特的功能配体。我们建议将GPR-CY4指定为CCR6。
Liver and activation-regulated chemokine (LARC) is a recently identified CC chemokine that is expressed mainly in the liver. LARC functions as a selective chemoattractant for lymphocytes that express a class of receptors specifically binding to LARC with high affinity. To identify the receptor for LARC, we examined LARC-induced calcium mobilization in cells stably expressing five CC chemokine receptors (CCR1-CCR5) and five orphan seven-transmembrane receptors. LARC specifically induced calcium flux in K562 cells as well as 293/EBNA-1 cells stably expressing an orphan receptor GPR-CY4. LARC induced migration in 293/EBNA-1 cells stably expressing GPR-CY4 with a bi-modal dose-response curve. LARC fused with secreted alkaline phosphatase (LARC-SEAP) bound specifically to Raji cells stably expressing GPR-CY4 with a K-d of 0.9 nM. Only LARC but not five other CC chemokines (MCP-1, RANTES, MIP-1 alpha, MIP-1 beta, and TARC) competed with LARC-SEAP for binding to GPR-CY4. By Northern blot analysis, GPR-CY4 mRNA was expressed mainly in speen, lymph nodes, appendix, and fetal liver among various human tissues. Among various leukocyte subsets, GPR-CY4 mRNA was detected in lymphocytes (CD4(+) and CD8(+) T cells and B cells) but not in natural killer cells, monocytes, or granulocytes. Expression of GPR-CY4 mRNA in CD4(+) and CD8(+) T cells was strongly up-regulated by IL-2. Taken together, GPR-CY4 is the specific receptor for LARC expressed selectively on lymphocytes, and LARC is a unique functional ligand for GPR-CY4. We propose GPR-CY4 to be designated as CCR6.