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-1β- or TNF-α-induced signaling molecules are potential diagnostic and therapeutic targets for preeclampsia.
Objective
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. Interventions and main outcome measures: 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.
Results
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 NH&sub2;-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 NH&sub2;-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-1β- or TNF-α-induced signaling molecules are potential diagnostic and therapeutic targets for preeclampsia.