Williams M A, Cave C M, Quaid G, Solomkin J S
Department of Surgery, University of Cincinnati College of Medicine, Ohio 45267-0558, USA.
Arch Surg. 1999 Dec;134(12):1360-6. doi: 10.1001/archsurg.134.12.1360.
Morbidity and even mortality correlate closely with major injury that causes a systemic inflammatory response. Cytokines and bioactive molecules present at the inflammatory site induce this response and regulate neutrophil proinflammatory responses. The CXC chemokines, important for neutrophil recruitment and activation, include interleukin 8 (IL-8), granulocyte chemotactic protein 2 (GCP-2), and epithelial cell-derived neutrophil attractant 78 (ENA-78). They induce neutrophil responses via 2 cell-surface receptors, CXCR-1 and CXCR-2. All 3 chemokines bind CXCR-2 with high affinity. Only IL-8 and GCP-2 bind CXCR-1 with high affinity.
The CXC chemokines regulate neutrophil responses differently.
Pretreatment of neutrophils from healthy volunteers with IL-8, GCP-2, or ENA-78; measured IL-8-induced migration; and tumor necrosis factor alpha (TNF-alpha)-induced peroxide production.
Flow cytometry and radioligand binding data indicate that IL-8, GCP-2, and ENA-78 equivalently reduced CXCR-1 and CXCR-2 cell surface expression by 34% to 54%. All treatments decreased affinity of both receptors 1.5- to 2-fold. However, only IL-8 pretreatment inhibited chemotaxis to 10-nmol/L IL-8 (mean +/- SE inhibition, 62%+/-6%). Although IL-8 and GCP-2, but not ENA-78, suppressed TNF-alpha-induced oxidant production (mean +/- SE inhibition, 42%+/-8% and 40%+/-23%, respectively), only GCP-2 inhibited the oxidative response to complement fragment C5a, and to the bacterial cell wall peptide N-formyl-methionyl-leucyl-phenylalanine.
The CXC chemokines regulate neutrophil proinflammatory functions differently. A thorough understanding of mechanisms for modulating neutrophil responses in inflammation will aid the development of interventions that reduce morbidity and mortality associated with severe trauma and sepsis.
发病率甚至死亡率与引起全身炎症反应的严重损伤密切相关。炎症部位存在的细胞因子和生物活性分子可诱导这种反应并调节中性粒细胞的促炎反应。对中性粒细胞募集和激活很重要的CXC趋化因子包括白细胞介素8（IL-8）、粒细胞趋化蛋白2（GCP-2）和上皮细胞衍生的中性粒细胞吸引剂78（ENA-78）。它们通过两种细胞表面受体CXCR-1和CXCR-2诱导中性粒细胞反应。所有这三种趋化因子都以高亲和力结合CXCR-2。只有IL-8和GCP-2以高亲和力结合CXCR-1。
CXC趋化因子对中性粒细胞反应的调节方式不同。
用IL-8、GCP-2或ENA-78预处理健康志愿者的中性粒细胞；测量IL-8诱导的迁移以及肿瘤坏死因子α（TNF-α）诱导的过氧化物产生。
流式细胞术和放射性配体结合数据表明，IL-8、GCP-2和ENA-78同等程度地使CXCR-1和CXCR-2细胞表面表达降低34%至54%。所有处理均使两种受体的亲和力降低1.5至2倍。然而，只有IL-8预处理抑制了对10 nmol/L IL-8的趋化作用（平均±标准误抑制率，62%±6%）。虽然IL-8和GCP-2（但不是ENA-78）抑制了TNF-α诱导的氧化剂产生（平均±标准误抑制率分别为42%±8%和40%±23%），但只有GCP-2抑制了对补体片段C5a以及细菌细胞壁肽N-甲酰甲硫氨酰亮氨酰苯丙氨酸的氧化反应。
CXC趋化因子对中性粒细胞促炎功能的调节方式不同。深入了解炎症中调节中性粒细胞反应的机制将有助于开发降低与严重创伤和脓毒症相关的发病率和死亡率的干预措施。
