NF kappa B and JNK/MAPK Activation Mediates the Production of Major Macrophage- or Dendritic Cell-Recruiting Chemokine in Human First Trimester Decidual Cells in Response to Proinflammatory Stimuli

作者：Li, Min; Wu, Zhen Ming; Yang, Hui; Huang, S Joseph^*

来源：Journal of Clinical Endocrinology & Metabolism, 2011, 96(8): 2502-2511.

DOI：10.1210/jc.2011-0055

Context: Preeclampsia is associated with elevated levels of proinflammatory cytokines, excess decidual macrophages, and dendritic cells. IL-1 beta- or TNF-alpha-stimulated leukocyte-free first trimester decidual cells produced abundant macrophage- and dendritic cell-recruiting chemokines identified in preeclamptic decidua.
Objective: The relative potency of IL-1 beta- or TNF-alpha-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.
Interventions and Main Outcome Measures: First trimester decidual cells were treated with estradiol + medroxyprogesterone acetate +/- IL-1 beta or TNF-alpha. 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 kappa B (NF kappa B) inhibitors.
Results: Neutralization of CCL2 and CCL5 significantly reduced chemotaxis of monocyte and dendritic cells up to 50 and 36%, respectively. NF kappa B and MAPK (MAPK kinase, JUN NH(2)-terminal kinase, p38 kinase) pathways were activated by IL-1 beta or TNF-alpha in first trimester decidual cells. In IL-1 beta- or TNF-alpha-stimulated first trimester decidual cells, NF kappa B inhibitor suppressed production of all six chemokines; JUN NH(2)-terminal kinase inhibitor inhibited secretion of CCL2, CCL4, and CCL5; and MAPK kinase and p38 inhibitor decreased production of CXCL8.
Conclusions: 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-1 beta- or TNF-alpha-induced signaling molecules are potential diagnostic and therapeutic targets for preeclampsia. (J Clin Endocrinol Metab 96: 2502-2511, 2011)

• 出版日期2011-8
• 单位上海交通大学