Struyf Sofie, Proost Paul, Vandercappellen Jo, Dempe Sebastian, Noyens Becky, Nelissen Sofie, Gouwy Mieke, Locati Massimo, Opdenakker Ghislain, Dinsart Christiane, Van Damme Jo
Laboratory of Molecular Immunology, Rega Institute for Medical Research, K.U. Leuven, Leuven, Belgium.
Eur J Immunol. 2009 Mar;39(3):843-57. doi: 10.1002/eji.200838660.
Chemokines mediate the inflammatory response by attracting various leukocyte types. MCP-2/CC chemokine ligand 8 (CCL8) was induced at only suboptimal levels in fibroblasts and endothelial cells by IL-1beta or IFN-gamma, unless these cytokines were combined. IFN-gamma also synergized with the TLR ligands peptidoglycan (TLR2), dsRNA (TLR3) or LPS (TLR4). Under these conditions, intact MCP-2/CCL8(1-76) produced by fibroblasts was found to be processed into MCP-2/CCL8(6-75), which lacked chemotactic activity for monocytic cells. Furthermore, the capacity of MCP-2/CCL8(6-75) to increase intracellular calcium levels through CCR1, CCR2, CCR3 and CCR5 was severely reduced. However, the truncated isoform still blocked these receptors for other ligands. MCP-2/CCL8(6-75) induced internalization of CCR2, inhibited MCP-1/CCL2 and MCP-2/CCL8 ERK signaling and antagonized the chemotactic activity of several CCR2 ligands (MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7). In contrast to MCP-3/CCL7, parvoviral delivery of MCP-2/CCL8 into B78/H1 melanoma failed to inhibit tumor growth, partially due to proteolytic cleavage into inactive MCP-2/CCL8 missing five NH(2)-terminal residues. However, in an alternative tumor model, using HeLa cells, MCP-2/CCL8 retarded tumor development. These data indicate that optimal induction and delivery of MCP-2/CCL8 is counteracted by converting this chemokine into a receptor antagonist, thereby losing its anti-tumoral potential.
趋化因子通过吸引各种白细胞类型来介导炎症反应。单核细胞趋化蛋白-2/CC趋化因子配体8（CCL8）在成纤维细胞和内皮细胞中仅在次优水平下由白细胞介素-1β或干扰素-γ诱导产生，除非将这些细胞因子联合使用。干扰素-γ还与Toll样受体（TLR）配体肽聚糖（TLR2）、双链RNA（TLR3）或脂多糖（TLR4）协同作用。在这些条件下，发现成纤维细胞产生的完整单核细胞趋化蛋白-2/CCL8（1-76）被加工成单核细胞趋化蛋白-2/CCL8（6-75），后者对单核细胞缺乏趋化活性。此外，单核细胞趋化蛋白-2/CCL8（6-75）通过CCR1、CCR2、CCR3和CCR5增加细胞内钙水平的能力严重降低。然而，这种截短的异构体仍然可以阻断其他配体与这些受体的结合。单核细胞趋化蛋白-2/CCL8（6-75）诱导CCR2内化，抑制单核细胞趋化蛋白-1/CCL2和单核细胞趋化蛋白-2/CCL8的细胞外信号调节激酶（ERK）信号传导，并拮抗几种CCR2配体（单核细胞趋化蛋白-1/CCL2、单核细胞趋化蛋白-2/CCL8、单核细胞趋化蛋白-3/CCL7）的趋化活性。与单核细胞趋化蛋白-3/CCL7不同，将单核细胞趋化蛋白-2/CCL8通过细小病毒载体导入B78/H1黑色素瘤细胞中未能抑制肿瘤生长，部分原因是其被蛋白水解切割成缺失五个氨基末端残基的无活性单核细胞趋化蛋白-2/CCL8。然而，在另一种肿瘤模型中，使用HeLa细胞时，单核细胞趋化蛋白-2/CCL8延缓了肿瘤的发展。这些数据表明，单核细胞趋化蛋白-2/CCL8的最佳诱导和递送会因该趋化因子转化为受体拮抗剂而受到阻碍，从而失去其抗肿瘤潜力。
