Down-regulation of neutrophil functions by the ELR+ CXC chemokine platelet basic protein
Down-regulation of neutrophil functions by the ELR+ CXC chemokine platelet basic protein
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DOI：
10.1182/blood.v96.9.2965.h8002965_2965_2972
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发表时间：
2000-11-01
期刊：
影响因子：
20.3
通讯作者：
Brandt, E
中科院分区：
文献类型：
--
作者：
Ehlert, JE;Ludwig, A;Brandt, E
血小板源性嗜血小板活化肽2 NAP-2（NAP-P，70个氨基酸）属于ELR+ CXC趋化因子亚家族，与该组的其他成员如IL-8类似，NAP-2激活中性粒细胞中的趋化性和脱粒（多形核白细胞[PMN]）通过趋化因子受体CXCR-1和CXCR-2，然而，血小板不分泌NAP-2作为活性趋化因子，而是作为缺乏PMN刺激能力的几种前体的C末端部分。正如我们以前所示，PMN本身可以通过蛋白水解从前体结缔组织激活肽III（CTAP-III，85个氨基酸）中释放NAP-2，而不是诱导细胞激活，在处理细胞周围的趋化因子的连续积累导致特异性表面表达的NAP-P结合位点的下调和趋化因子诱导的PMN脱粒的脱敏。因此，NAP-P前体可被视为中性粒细胞功能脱敏的间接介质。在目前的研究中，我们研究了另一种主要的NAP-2前体，血小板碱性蛋白（PBP，94个氨基酸）的生物学影响。我们表明，PBP是相当有效的比CTAP-III脱敏脱粒和趋化性在中性粒细胞，我们目前的数据表明，高脱敏能力的PBP是基于其增强的蛋白水解裂解成NAP-2的嗜中性粒细胞表达的组织蛋白酶G，它涉及有效下调表面表达的CXCR-2，而CXCR-1几乎没有受到影响。相应地，我们发现PBP和CTAP-III抑制中性粒细胞对NAP-2的CXCR-2依赖性趋化性，但不抑制CXCR-1依赖性趋化性。总之，我们的研究结果表明，NAP-2的抗炎能力是由其前体的种类。(C)2000年，美国血液学会。
The platelet-derived neutrophil-activating peptide 2 (NAP-P, 70 amino acids) belongs to the ELR+ CXC subfamily of chemokines, Similar to other members of this group, such as IL-8, NAP-2 activates chemotaxis and degranulation in neutrophils (polymorphonuclear [PMN]) through chemokine receptors CXCR-1 and CXCR-2, However, platelets do not secrete NAP-2 as an active chemokine but as the C-terminal part of several precursors that lack PMN-stimulating capacity. As we have previously shown, PMN themselves may liberate NAP-2 from the precursor connective tissue-activating peptide III(CTAP-III, 85 amino acids) by proteolysis, Instead of inducing cell activation, continuous accumulation of the chemokine in the surroundings of the processing cells results in the down-regulation of specific surface-expressed NAP-P binding sites and in the desensitization of chemokine-induced PMN degranulation. Thus, NAP-P precursors may be regarded as indirect mediators of functional desensitization in neutrophils. In the current study we investigated the biologic impact of another major NAP-2 precursor, the platelet basic protein (PBP, 94 amino acids). We show that PBP is considerably more potent than CTAP-III to desensitize degranulation and chemotaxis in neutrophils, We present data suggesting that the high desensitizing capacity of PBP is based on its enhanced proteolytic cleavage into NAP-2 by neutrophile-expressed cathepsin G and that it involves efficient down-regulation of surface-expressed CXCR-2 while CXCR-1 is hardly affected. Correspondingly, we found PBP and, less potently, CTAP-III to inhibit CXCR-2- but not CXCR-1-dependent chemotaxis of neutrophils toward NAP-2. Altogether our findings demonstrate that the anti-inflammatory capacity of NAP-2 is governed by the species of its precursors. (C) 2000 by The American Society of Hematology.