Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University, New Haven, Connecticut 06520, USA.
J Clin Endocrinol Metab. 2011 Aug;96(8):2502-11. doi: 10.1210/jc.2011-0055. Epub 2011 Jun 15.
Preeclampsia is associated with elevated levels of proinflammatory cytokines, excess decidual macrophages, and dendritic cells. IL-1β- or TNF-α-stimulated leukocyte-free first trimester decidual cells produced abundant macrophage- and dendritic cell-recruiting chemokines identified in preeclamptic decidua.
The relative potency of IL-1β- or TNF-α-induced first trimester decidual cell-secreted chemokines in chemoattracting macrophages or dendritic cells and the signaling pathways involved in the expression of these chemokines were evaluated.
First trimester decidual cells were treated with estradiol + medroxyprogesterone acetate ± IL-1β or TNF-α. The chemotaxis assay was performed by incubating conditioned medium from first trimester decidual cells with neutralizing antibody for six chemokines. The activation of each signaling pathway was examined by Western blotting, flow cytometry, confocal microscopy, and ELISA with or without kinase and nuclear factor κB (NFκB) inhibitors.
Neutralization of CCL2 and CCL5 significantly reduced chemotaxis of monocyte and dendritic cells up to 50 and 36%, respectively. NFκB and MAPK (MAPK kinase, JUN NH₂-terminal kinase, p38 kinase) pathways were activated by IL-1β or TNF-α in first trimester decidual cells. In IL-1β- or TNF-α-stimulated first trimester decidual cells, NFκB inhibitor suppressed production of all six chemokines; JUN NH₂-terminal kinase inhibitor inhibited secretion of CCL2, CCL4, and CCL5; and MAPK kinase and p38 inhibitor decreased production of CXCL8.
Up-regulation of CCL2 and CCL5 by first trimester decidual cells in response to proinflammatory stimuli may account for the accumulation of macrophages and dendritic cells in preeclamptic decidua. These chemokines and underlying IL-1β- or TNF-α-induced signaling molecules are potential diagnostic and therapeutic targets for preeclampsia.
子痫前期与促炎细胞因子水平升高、蜕膜巨噬细胞和树突状细胞增多有关。白细胞游离的第一孕期蜕膜细胞在白细胞介素-1β（IL-1β）或肿瘤坏死因子-α（TNF-α）刺激下产生丰富的招募巨噬细胞和树突状细胞的趋化因子，这些趋化因子在子痫前期蜕膜中被鉴定出来。
评估 IL-1β 或 TNF-α 诱导的第一孕期蜕膜细胞分泌的趋化因子在招募巨噬细胞或树突状细胞中的相对效力，以及参与这些趋化因子表达的信号通路。
用雌二醇+醋酸甲羟孕酮+IL-1β 或 TNF-α处理第一孕期蜕膜细胞。通过将第一孕期蜕膜细胞的条件培养基与六种趋化因子的中和抗体孵育，进行趋化实验。用或不用激酶和核因子κB（NFκB）抑制剂，通过 Western 印迹、流式细胞术、共聚焦显微镜和 ELISA 检查每种信号通路的激活情况。
CCL2 和 CCL5 的中和显著降低单核细胞和树突状细胞的趋化性，分别达到 50%和 36%。IL-1β 或 TNF-α在第一孕期蜕膜细胞中激活 NFκB 和丝裂原激活蛋白激酶（丝裂原激活蛋白激酶激酶、JUN NH₂-末端激酶、p38 激酶）通路。在 IL-1β 或 TNF-α刺激的第一孕期蜕膜细胞中，NFκB 抑制剂抑制所有六种趋化因子的产生；JUN NH₂-末端激酶抑制剂抑制 CCL2、CCL4 和 CCL5 的分泌；而丝裂原激活蛋白激酶激酶和 p38 抑制剂则降低 CXCL8 的产生。
第一孕期蜕膜细胞对促炎刺激的 CCL2 和 CCL5 的上调可能导致子痫前期蜕膜中巨噬细胞和树突状细胞的积累。这些趋化因子和潜在的 IL-1β 或 TNF-α诱导的信号分子是子痫前期的潜在诊断和治疗靶点。
