title: NFκB 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.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  METHODS
  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 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.
  
  
  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.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Zhen-Ming
authors.initials: ZM
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Huang
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases