The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3
The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3
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DOI：
10.1074/jbc.m005652200
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发表时间：
2001-02-02
影响因子：
4.8
通讯作者：
Clark-Lewis, I
中科院分区：
文献类型：
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作者：
Loetscher, P;Pellegrino, A;Clark-Lewis, I
Th1和Th2淋巴细胞表达不同的趋化因子受体（CCRs）， CXCR3是I-TAG（干扰素诱导的T细胞α -趋化剂）、Mig （γ -干扰素诱导的单因子）和IP10（干扰素诱导蛋白10）的受体，优先表达在Th1细胞上，而CCR3是eotaxin和其他几种CC趋化因子的受体，是Th2细胞的特征。在研究这两种受体介导的反应时，我们发现CXCR3的激动剂可以作为CCR3的拮抗剂。I-TAG、Mig和IP10竞争eotaxin与ccr3承载细胞的结合，并抑制由eotaxin、eotanin-2、MCP-S（单核细胞趋化蛋白-2）、MCP-S、MCP-4和RANTES（通过激活正常T细胞表达和分泌而调节）刺激引起的细胞迁移和Ca2+变化。通过将eotaxin的前8个nh2末端残基替换为与I-TAG结合的CCR3产生的一种杂交趋化因子，其亲和力分别比eotaxin或I-TAG高3倍和10倍。该杂种作为eotaxin活性抑制剂的效力是I-TAG的5倍，并且在低至5 nM的浓度下有效。所描述的拮抗剂均未诱导CCR3内化，这表明它们缺乏激动作用，因此可以作为纯拮抗剂。这些结果表明，趋化因子通过CXCR3吸引Th1细胞，可以同时阻断Th2细胞响应CCR3配体的迁移，从而增强T细胞募集的极化。
Th1 and Th2 lymphocytes express a different repertoire of chemokine receptors (CCRs), CXCR3, the receptor for I-TAG (interferon-inducible T cell alpha -chemoattractant), Mig (monokine induced by gamma -interferon), and IP10 (interferon-inducible protein 10), is expressed preferentially on Th1 cells, whereas CCR3, the receptor for eotaxin and several other CC chemokines, is characteristic of Th2 cells. While studying responses that are mediated by these two receptors, we found that the agonists for CXCR3 act as antagonists for CCR3. I-TAG, Mig, and IP10 compete for the binding of eotaxin to CCR3-bearing cells and inhibit migration and Ca2+ changes induced in such cells by stimulation with eotaxin, eotanin-2, MCP-S (monocyte chemottractant protein-2), MCP-S, MCP-4, and RANTES (regulated on activation normal T cell expressed and secreted). A hybrid chemokine generated by substituting the first eight NH2-terminal residues of eotaxin with those of I-TAG bound CCR3 with higher affinity than eotaxin or I-TAG (3- and 10-fold, respectively). The hybrid was 5-fold more potent than I-TAG as an inhibitor of eotaxin activity and was effective at concentrations as low as 5 nM. None of the antagonists described induced the internalization of CCR3, indicating that they lack agonistic effects and thus qualify as pure antagonists. These results suggest that chemokines that attract Th1 cells via CXCR3 can concomitantly block the migration of Th2 cells in response to CCR3 ligands, thus enhancing the polarization of T cell recruitment.