IL-6 and IL-8 release is mediated via multiple signaling pathways after stimulating dendritic cells with lysophospholipids
IL-6 and IL-8 release is mediated via multiple signaling pathways after stimulating dendritic cells with lysophospholipids
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DOI：
10.1189/jlb.1205751
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发表时间：
2006-08-01
影响因子：
5.5
通讯作者：
Maghazachi, Azzam A.
中科院分区：
文献类型：
--
作者：
Oz-Arslan, Devrim;Ruscher, Wolfgang;Maghazachi, Azzam A.
溶血磷脂酸（LPA）和1-磷酸鞘氨醇（SIP）是具有生物活性的脂质介质，已知它们在过敏反应以及肿瘤发病机制中起主要作用。在这里，这些溶血磷脂（LPLs）在树突状细胞（DC）的生物活性和信号通路的进一步特点。流式细胞术和免疫印迹分析表明，未成熟和成熟DC表达LPL受体S1 P（1）、S1 P（3）、SIP 3和LPA（2），但不表达S1 P（2）、S1 P（4）、LPA（1）或LPA（3）。此外，酶联免疫吸附测定实验表明，同时添加这些LPL的脂多糖的存在下，未成熟的DC中的炎性细胞因子白细胞介素（IL）-6和IL-8的分泌增强成熟的DC。相比之下，在成熟DC暴露于单独的LPL后，没有观察到IL-6或IL-8释放的改变。此外，百日咳毒素和丝裂原活化蛋白激酶（MAPK）激酶抑制剂PD 98059的研究表明，G（i）蛋白和MAPK通路参与了这些LPL诱导的细胞反应。为了证实这些发现，我们观察到LPL在未成熟DC中诱导细胞外信号调节激酶1/2的磷酸化，但在成熟DC中不诱导。进一步的分析显示磷脂酶D、Rho和蛋白激酶C的抑制剂也抑制了LPL诱导的IL-6和IL-8的释放。因此，我们的研究结果表明，在成熟过程中，树突状细胞中的脂多糖从信号转导机制中解偶联LPL受体，并且在成熟树突状细胞的早期时间点暴露LPL改变成熟树突状细胞的促炎能力。J. Leukoc. 80：287-297; 2006.
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (SIP) are bioactive lipid mediators, which are known to play major roles in allergic reactions as well as in tumor pathogenesis. Here, the biological activities and signal pathways of these lysophospholipids (LPLs) in dendritic cells (DCs) were characterized further. Flow cytometric and immunoblot analyses indicate that immature as well as mature DCs express the LPL receptors S1P(1), S1P(3), SIP3, and LPA(2), but not S1P(2), S1P(4), LPA(1), or LPA(3). Moreover, enzyme-linked immunosorbent assay experiments demonstrate that simultaneous addition of these LPLs to immature DCs in the presence of lipopolysaccharide enhanced the secretion of the inflammatory cytokines interleukin (IL)-6 and IL-8 in maturing DCs. In contrast, no modification of IL-6 or IL-8 release was observed after exposure of mature DCs to LPLs alone. In addition, studies with pertussis toxin and mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 suggested that G(i) proteins and MAPK pathway are involved in these LPL-induced cell responses. Corroborating these findings, we observed that LPLs induce the phosphorylation of extracellular signal-regulated kinase 1/2 in immature DCs but not in mature DCs. Further analyses show that inhibitors of phosholipase D, Rho, and protein kinase C also inhibited the LPL-induced release of IL-6 and IL-8. Therefore, our findings suggest that lipopolysaccharide in DCs uncouples LPL receptors from the signal-transducing machinery during maturation and that exposure of LPLs at early time-points to maturing DCs modifies the proinflammatory capacity of mature DCs. J. Leukoc. Biol. 80: 287-297; 2006.