Khandaker M H, Xu L, Rahimpour R, Mitchell G, DeVries M E, Pickering J G, Singhal S K, Feldman R D, Kelvin D J
Department of Microbiology and Immunology, University of Western Ontario, London, Canada.
J Immunol. 1998 Aug 15;161(4):1930-8.
The expression of the seven-transmembrane domain chemokine receptors CXCR1 and CXCR2 modulates neutrophil responsiveness to the chemoattractant IL-8 and a number of closely related CXC chemokines. In the present study, we investigated the mechanism by which bacterial LPS induces the down-modulation of IL-8 responsiveness and CXCR1 and CXCR2 expression on human neutrophils. Treating neutrophils with LPS reduced IL-8R expression to 55 +/- 5% of the control within 30 min and to 23 +/- 2% within 1 h of stimulation. Furthermore, this down-modulation could not be attributed to increased concentrations of IL-8, TNF-alpha, or IL-1beta, since ELISA studies indicated that LPS-stimulated neutrophils did not release detectable amounts of these proteins before 2 h poststimulation. The tyrosine kinase (TK) inhibitors genistein and herbimycin A attenuated the LPS-mediated down-modulation of CXCR1 and CXCR2, indicating that the activation of a TK is required for LPS to mediate its effect. The effect of LPS on receptor expression paralleled the hyperphosphorylation of the protein TK p72syk. Although IL-8 induced a comparable down-modulation of CXCR1 and CXCR2, TK inhibitors did not attenuate this effect. These studies provide the first evidence of an agonist-independent, TK-dependent pathway of chemokine receptor regulation by endotoxin.
七跨膜结构域趋化因子受体CXCR1和CXCR2的表达调节中性粒细胞对趋化因子IL-8及一些密切相关的CXC趋化因子的反应性。在本研究中，我们调查了细菌脂多糖（LPS）诱导人中性粒细胞上IL-8反应性下调以及CXCR1和CXCR2表达下调的机制。用LPS处理中性粒细胞，在30分钟内可使IL-8R表达降至对照的55±5%，刺激1小时内降至23±2%。此外，这种下调不能归因于IL-8、肿瘤坏死因子-α（TNF-α）或白细胞介素-1β（IL-1β）浓度的增加，因为酶联免疫吸附测定（ELISA）研究表明，LPS刺激的中性粒细胞在刺激后2小时之前不会释放可检测量的这些蛋白质。酪氨酸激酶（TK）抑制剂染料木黄酮和除莠霉素A减弱了LPS介导的CXCR1和CXCR2下调，表明LPS介导其效应需要TK激活。LPS对受体表达的影响与蛋白质TK p72syk的过度磷酸化平行。尽管IL-8诱导了CXCR1和CXCR2类似的下调，但TK抑制剂并未减弱这种效应。这些研究首次证明了内毒素通过一种不依赖激动剂、依赖TK的途径调节趋化因子受体。
