Louahed Jamila, Struyf Sofie, Demoulin Jean-Baptiste, Parmentier Marc, Van Snick Jacques, Van Damme Jo, Renauld Jean-Christophe
Ludwig Institute for Cancer Research, Brussels branch, Experimental Medicine Unit, Université de Louvain, Brussels, Belgium.
Eur J Immunol. 2003 Feb;33(2):494-501. doi: 10.1002/immu.200310025.
We have previously shown that the CC-chemokine 1-309 (CCL1) protects mouse thymic lymphomas against corticoid-induced apoptosis. Here, we analyzed the signal transduction pathways involved in this activity on BW5147 lymphoma. Inhibition of the CCL1 activity by pertussis toxin suggested the involvement of a G protein-coupled chemokine receptor. The role of CCR8 was supported by the observation that vMIP-I, another CCR8-ligand identified from the genome of a T cell transforming herpes virus, shared CCL1 anti-apoptotic activity. In addition to CCR8, BW5147 cells also expressed the CXCR4 receptor but its ligand, SDF-1 (CXCL12) showed only a modest anti-apoptotic activity. Other chemokines acting on CCR2, CCR4 and CCR5 failed to protect against apoptosis and to induce BW5147 chemotaxis, suggesting that these receptors were not functionally expressed. By contrast, both CCL1 and vMIP-I up-regulated ERK1/2 MAPK phosphorylation in BW5147 cells. Further analysis demonstrated that CCL1 activates the MAPK pathway in CCR8-transfected CHO cells. The implication of this pathway was confirmed by the fact that PD98059, an inhibitor of MEK kinases, as well as a dominant negative isoform of the M-RAS protein specifically blocked the anti-apoptotic activity of CCL1.
我们之前已经表明，CC趋化因子1-309（CCL1）可保护小鼠胸腺淋巴瘤免受皮质激素诱导的细胞凋亡。在此，我们分析了参与BW5147淋巴瘤这一活性的信号转导途径。百日咳毒素对CCL1活性的抑制表明存在一种G蛋白偶联趋化因子受体参与其中。从一种T细胞转化疱疹病毒基因组中鉴定出的另一种CCR8配体vMIP-I具有CCL1的抗凋亡活性，这一观察结果支持了CCR8的作用。除CCR8外，BW5147细胞还表达CXCR4受体，但其配体SDF-1（CXCL12）仅表现出适度的抗凋亡活性。作用于CCR2、CCR4和CCR5的其他趋化因子未能保护细胞免受凋亡，也未能诱导BW5147细胞趋化，这表明这些受体未功能性表达。相比之下，CCL1和vMIP-I均上调了BW5147细胞中ERK1/2 MAPK的磷酸化水平。进一步分析表明，CCL1在CCR8转染的CHO细胞中激活MAPK途径。MEK激酶抑制剂PD98059以及M-RAS蛋白的显性负性异构体特异性阻断CCL1的抗凋亡活性，这一事实证实了该途径的作用。
