Proteolytic activation of alternative CCR1 ligands in inflammation
Proteolytic activation of alternative CCR1 ligands in inflammation
复制标题
DOI：
10.4049/jimmunol.174.11.7341
复制
发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Schall, TJ
中科院分区：
文献类型：
--
作者：
Berahovich, RD;Miao, ZH;Schall, TJ
尽管趋化因子CCL 3/MIP-1 α和CCL 5/RANTES被认为是炎症反应中的主要CCR 1配体，但也描述了替代的CCR 1配体。事实上，四种这样的趋化因子，CCL 6/C10/MIP-相关蛋白-1，CCL 9/MIP-1 γ/MIP-相关蛋白-2，CCL 15/MIP-1 δ/血液滤液CC趋化因子-2/白细胞趋化素-1，和CCL 23/CK β 8/骨髓祖细胞抑制因子-1，是独特的，具有单独编码的16-20个残基的N-末端结构域和形成第三个二硫桥的两个另外的精确定位的半胱氨酸。在体外，这四种趋化因子是弱的CCR 1激动剂，但通过工程改造或表达相关的N-末端截短可以使效力增加高达1000倍。我们研究了促炎蛋白酶、人细胞上清液或生理液体对这些趋化因子进行N端截短从而激活其功能的能力。值得注意的是，大多数蛋白酶和流体从所有四种趋化因子中去除N-末端结构域，但相对不能进一步切割截短形式。截短的趋化因子在体外CCR 1介导的信号传导和趋化性测定中表现出高达1000倍的增加。此外，在类风湿性关节炎患者的滑液中检测到相对高水平的N-末端截短的CCL 15/MIP-1 δ和CCL 23/CK β 8，而不是CCL 3/MIP-1 α或CCL 5/RANTES。这些数据表明，替代CCR 1配体转化为有效的趋化蛋白酶释放过程中在体内炎症反应。
Although chemokines CCL3/MIP-1 alpha and CCL5/RANTES are considered to be primary CCR1 ligands in inflammatory responses, alternative CCR1 ligands have also been described. Indeed, four such chemokines, CCL6/C10/MIP-related protein-1, CCL9/MIP-1 gamma/MIP-related protein-2, CCL15/MIP-1 delta/hemofiltrate CC chemokine-2/leukotactin-1, and CCL23/CK beta 8/myeloid progenitor inhibitory factor-1, are unique in possessing a separately encoded N-terminal domain of 16-20 residues and two additional precisely positioned cysteines that form a third disulfide bridge. In vitro, these four chemokines are weak CCR1 agonists, but potency can be increased up to 1000-fold by engineered or expression-associated N-terminal truncations. We examined the ability of proinflammatory proteases, human cell supernatants, or physiological fluids to perform N-terminal truncations of these chemokines and thereby activate their functions. Remarkablyj most of the proteases and fluids removed the N-terminal domains from all four chemokines, but were relatively unable to cleave the truncated forms further. The truncated chemokines exhibited up to 1000-fold increases in CCR1-mediated signaling and chemotaxis assays in vitro. In addition, N-terminally truncated CCL15/MIP-1 delta and CCL23/CK beta 8, but not CCL3/MIP-1 alpha or CCL5/RANTES, were detected at relatively high levels in synovial fluids from rheumatoid arthritis patients. These data suggest that alternative CCR1 ligands are converted into potent chemoattractants by proteases released during inflammatory responses in vivo.