Mmatory cytokine-enhanced aberrant MMP expression in firsttrimester decidual cells, that are implicated in advertising the shallow EVT invasion of PE. Constant with this supposition, the current ELISA measurements indicate that, in firsttrimester decidual cells incubated with E2 MPA, coincubation with IFN-g virtually eliminated the marked upregulation of MMP-1, MMP-3, and MMP-9 by TNF-a, as confirmed by substrate gel electrophoresis and RT-qPCR. Immunoblotting revealed that p38 MAPK signaling mediates TNF-aeinduced MMP-1, MMP-3, and MMP-9 expression, whereas IFN-g significantly reverses these TNF-a effects by inhibiting p38 MAPK phosphorylation. In summary, new in situ and in vitro observations indicate that aberrant TNF-aeaugmented expression of MMP-1, MMP-3, and MMP-9 by decidual cells could interfere with typical stepwise ITG-mediated EVT invasion on the decidua to promote the later onset of PE. Furthermore, IFN-g reverses this abnormal TNF-aeenhanced expression (Figure eight). These IFN-g effects are consistent with restoration of regular stepwise EVT invasion of the decidua and recommend a mechanism by which dNK cellederived IFN-g counteracts the shallow trophoblast invasion strongly implicated in impaired decidual vascular remodeling, major to the later development of PE.ten. Bulla R, Villa A, Bossi F, Cassetti A, Radillo O, Spessotto P, De Seta F, Guaschino S, Tedesco F: VE-cadherin is often a important molecule for trophoblast-endothelial cell interaction in decidual spiral arteries. Exp Cell Res 2005, 303:101e113 11. Huppertz B, Kertschanska S, Demir AY, Frank HG, Kaufmann P: Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) through trophoblast invasion in the human placenta. Cell Tissue Res 1998, 291:133e148 12. Nagase H, Woessner JF Jr: Matrix metalloproteinases.Eptinezumab J Biol Chem 1999, 274:21491e21494 13. Nagase H, Visse R, Murphy G: Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006, 69:562e573 14. Lijnen HR: Matrix metalloproteinases and cellular fibrinolytic activity. Biochemistry (Mosc) 2002, 67:92e98 15. Lockwood CJ, Oner C, Uz YH, Kayisli UA, Huang SJ, Buchwalder LF, Murk W, Funai EF, Schatz F: Matrix metalloproteinase 9 (MMP9) expression in preeclamptic decidua and MMP9 induction by tumor necrosis aspect alpha and interleukin 1 beta in human initial trimester decidual cells. Biol Reprod 2008, 78: 1064e1072 16. Sibai B, Dekker G, Kupferminc M: Pre-eclampsia.Belumosudil Lancet 2005, 365: 785e799 17.PMID:24065671 Lockwood CJ, Matta P, Krikun G, Koopman LA, Masch R, Toti P, Arcuri F, Huang ST, Funai EF, Schatz F: Regulation of monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha and interleukin-1beta in very first trimester human decidual cells: implications for preeclampsia. Am J Pathol 2006, 168: 445e452 18. Yeh CC, Chao KC, Huang SJ: Innate immunity, decidual cells, and preeclampsia. Reprod Sci 2013, 20:339e353 19. Huang S, Chen CP, Schatz F, Rahman M, Abrahams V, Lockwood C: Pre-eclampsia is linked to dendritic cell recruitment into the uterine decidua. J Pathol 2008, 214:328e336 20. Wu ZM, Yang H, Li M, Yeh CC, Schatz F, Lockwood CJ, Di W, Huang SJ: Pro-inflammatory cytokine-stimulated very first trimester decidual cells enhance macrophage-induced apoptosis of extravillous trophoblasts. Placenta 2012, 33:188e194 21. Nathan CF: Secretory merchandise of macrophages. J Clin Invest 1987, 79:319e326 22. Itoh Y, Nagase H: Preferential inactivation of tissue inhibitor.
