Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator
Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator
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DOI：
10.4049/jimmunol.174.9.5243
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发表时间：
2005-05-01
影响因子：
4.4
通讯作者：
Krensky, AM
中科院分区：
文献类型：
--
作者：
Deng, AM;Chen, SX;Krensky, AM
颗粒溶素是一种由活化的人CTL和NK细胞产生的阳离子蛋白，对微生物和肿瘤靶标具有细胞溶解性。在这项研究中，我们表明，颗粒溶解素也作为一种化学引诱剂，并激活单核细胞产生细胞因子/趋化因子。虽然颗粒溶素介导的细胞毒性发生在微摩尔浓度，化学吸引发生在纳摩尔范围内，免疫激活发生在广泛的浓度范围内（纳摩尔至微摩尔）。颗粒溶素导致单核细胞、CD 4（+）和CD 8（+）记忆（CD 45 RO）而非初始（CD 45 RA）T细胞、NK细胞和成熟（而非未成熟）单核细胞来源的树突状细胞的趋化性增加2- 7倍。百日咳毒素治疗消除了颗粒溶解素的化学吸引作用，表明G蛋白偶联受体的参与。在低浓度（10 nM）下，颗粒溶素促进单核细胞和U937细胞产生的MCP-1和RANTES增加3至10倍，而LPS刺激的单核细胞产生的TNF-α增加2倍需要更高浓度的颗粒溶素（微摩尔）。总之，这些数据表明，颗粒溶解素的局部浓度对于生物活性是至关重要的，高浓度导致细胞毒性，而较低浓度，可能更远离颗粒溶解素释放部位，主动将免疫细胞募集到炎症部位。
Granulysin, a cationic protein produced by activated human CTL and NK cells, is cytolytic against microbial and tumor targets. In this study we show that granulysin also functions as a chemoattractant and activates monocytes to produce cytokines/chemokines. Although granulysin-mediated cytotoxicity occurs at micromolar concentrations, chemoattraction occurs in the nanomolar range, and immune activation occurs over a wide range of concentrations (nanomolar to micromolar). Granulysin causes a 2- to 7-fold increase in chemotaxis of monocytes, CD4(+), and CD8(+) memory (CD45RO) but not naive (CD45RA) T cells, NK cells, and mature, but not immature, monocyte-derived dendritic cells. Pertussis toxin treatment abrogates chemoattraction by granulysin, indicating involvement of G-protein-coupled receptor(s). At low concentrations (10 nM), granulysin promotes a 3- to 10-fold increase in MCP-1 and RANTES produced by monocytes and U937 cells, while a 2-fold increase in TNF-alpha production by LPS-stimulated monocytes requires higher concentrations of granulysin (micromolar). Taken together, these data indicate that the local concentration of granulysin is critical for the biologic activity, with high concentrations resulting in cytotoxicity while lower concentrations, presumably further from the site of granulysin release, actively recruit immune cells to sites of inflammation.