Nasser Mohd W, Raghuwanshi Sandeep K, Grant Delores J, Jala Venkatakrishna R, Rajarathnam Krishna, Richardson Ricardo M
Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA.
J Immunol. 2009 Sep 1;183(5):3425-32. doi: 10.4049/jimmunol.0900305. Epub 2009 Aug 10.
CXCL8 (also known as IL-8) activates CXCR1 and CXCR2 to mediate neutrophil recruitment and trigger cytotoxic effect at sites of infection. Under physiological conditions, CXCL8 could exist as monomers, dimers, or a mixture of monomers and dimers. Therefore, both forms of CXCL8 could interact with CXCR1 and CXCR2 with different affinities and potencies to mediate different cellular responses. In the present study, we have used a "trapped" nonassociating monomer (L25NMe) and a nondissociating dimer (R26C) to investigate their activities for human neutrophils that express both receptors and for RBL-2H3 cells stably expressing either CXCR1(RBL-CXCR1) or CXCR2 (RBL-CXCR2). The monomer was more active than the dimer for activities such as intracellular Ca(2+) mobilization, phosphoinositide hydrolysis, chemotaxis. and exocytosis. Receptor regulation, however, is distinct for each receptor. The rate of monomer-mediated regulation of CXCR1 is greater for activities such as phosphorylation, desensitization, beta-arrestin translocation, and internalization. In contrast, for CXCR2, both monomeric and dimeric CXCL8 mediate these activities to a similar extent. Interestingly, receptor-mediated signal-regulated kinase (ERK) phosphorylation in response to all three CXCL8 variants was more sustained for CXCR2 relative to CXCR1. Taken together, the results indicate that the CXCL8 monomer and dimer differentially activate and regulate CXCR1 and CXCR2 receptors. These distinct properties of the ligand and the receptors play a critical role in orchestrating neutrophil recruitment and eliciting cytotoxic activity during an inflammatory response.
CXCL8（也称为白细胞介素-8）激活CXCR1和CXCR2，以介导中性粒细胞募集并在感染部位触发细胞毒性作用。在生理条件下，CXCL8可以以单体、二聚体或单体与二聚体的混合物形式存在。因此，两种形式的CXCL8都可以以不同的亲和力和效力与CXCR1和CXCR2相互作用，从而介导不同的细胞反应。在本研究中，我们使用了一种“捕获”的非缔合单体（L25NMe）和一种非解离二聚体（R26C），来研究它们对同时表达这两种受体的人中性粒细胞以及稳定表达CXCR1（RBL-CXCR1）或CXCR2（RBL-CXCR2）的RBL-2H3细胞的活性。在诸如细胞内Ca(2+)动员、磷酸肌醇水解、趋化作用和胞吐作用等活性方面，单体比二聚体更具活性。然而，每种受体的受体调节是不同的。对于诸如磷酸化、脱敏、β-抑制蛋白易位和内化等活性，单体介导的CXCR1调节速率更高。相比之下，对于CXCR2，单体和二聚体形式的CXCL8介导这些活性的程度相似。有趣的是，相对于CXCR1，响应于所有三种CXCL8变体的受体介导的信号调节激酶（ERK）磷酸化在CXCR2中更持久。综上所述，结果表明CXCL8单体和二聚体对CXCR1和CXCR2受体的激活和调节存在差异。配体和受体的这些不同特性在炎症反应过程中协调中性粒细胞募集和引发细胞毒性活性方面起着关键作用。
