Differential modes of regulation of CXC chemokine-induced internalization and recycling of human CXCR1 and CXCR2
Differential modes of regulation of CXC chemokine-induced internalization and recycling of human CXCR1 and CXCR2
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DOI：
10.1006/cyto.1999.0510
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发表时间：
1999-12-01
期刊：
影响因子：
3.8
通讯作者：
Ben-Baruch, A
中科院分区：
文献类型：
--
作者：
Feniger-Barish, R;Ran, M;Ben-Baruch, A
对人中性粒细胞IL-8受体CXCR 1和CXCR 2的研究表明，这两种受体受ELR+-CXC趋化因子的不同调节，它们在功能上不同，在介导炎症过程中可能具有不同的作用。为了阐明CXCR 1和CXCR 2在炎症中的作用，并阐明IL-8和NAP-2对这些受体的不同调节的基础，我们表征了IL-8和NAP-2诱导的调节每个受体表达的机制，重点是受体内化和再循环。使用HEK 293细胞转染子，显示IL-8比NAP-2诱导显著更高水平的CXCR 2内化。此外，尽管CXCR 2以类似的高亲和力结合IL-8和NAP-2，但IL-8在功能上与NAP-2竞争并取代NAP-2，并促使高水平的内化，类似于单独IL-8诱导的内化。在一个系统中，提供了一个相同的细胞环境，CXCR 1和CXCR 2之间的可靠比较，我们已经表明，控制CXCR 1的内化机制不同于那些调节CXCR 2内化。而IL-8诱导的CXCR 1的内化是深刻地依赖于一个区域的羧基末端表达6个磷酸化位点，CXCR 2的内化主要是由膜近端结构域的羧基末端，不表达磷酸化位点。质膜上受体再表达的分析表明，在去除游离配体并在37 ℃下孵育细胞后的早期时间点，受体再循环导致CXCR 1和CXCR 2表达的恢复，而在稍后的时间点，其他过程可能参与受体再表达。磷酸化独立的机制被证明是直接两个受体的回收途径。IL-8和NAP-2对CXCR 1与CXCR 2内化的差异控制以及磷酸化介导的机制表明，趋化因子和受体特异性内化调节模式可能有助于这些受体的不同活性。(C)北京：科学出版社.
Studies of human neutrophil IL-8 receptors, CXCR1 and CXCR2, have shown that the two receptors are differentially regulated by ELR+-CXC chemokines, that they differ functionally and may have diverse roles in mediating the inflammatory process. To elucidate the role of CXCR1 and CXCR2 in inflammation and to delineate the basis for the divergent regulation of these receptors by IL-8 and NAP-2, we characterized the IL-8- and NAP-2-induced mechanisms regulating the expression of each receptor, focusing on receptor internalization and recycling. Using HEK 293 cell transfectants, IL-8 was shown to induce significantly higher levels of CXCR2 internalization than NAP-2, Moreover, although CXCR2 bound IL-8 and NAP-2 with similarly high affinity, IL-8 functionally competed with and displaced NAP-2, and prompted high levels of internalization, similar to those induced by IL-8 alone. In a system providing an identical cellular milieu far reliable comparisons between CXCR1 and CXCR2, we have shown that the mechanisms controlling the internalization of CXCR1 diverge from those regulating CXCR2 internalization. Whereas IL-8-induced internalization of CXCR1 was profoundly dependent on a region of the carboxyl terminus expressing six phosphorylation sites, internalization of CXCR2 was primarily regulated by a membrane proximal domain of the carboxyl terminus that does not express phosphorylation sites. Analysis of receptor re-expression on the plasma membrane indicated that at early time points following removal of free ligand and incubation of the cells at 37 degrees C, receptor recycling accounted for recovery of CXCR1 and CXCR2 expression, whereas at later time points other processes may be involved in receptor re-expression. Phosphorylation-independent mechanisms were shown to direct both receptors to the recycling pathway. The differential control of CXCR1 vs CXCR2 internalization by IL-8 and NAP-2, as well as by phosphorylation-mediated mechanisms, suggests that a chemokine and receptor-specific mode of regulation of internalization may contribute to the divergent activities of these receptors. (C) 1999 Academic Press.