Nuclear factor-κB, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress -: Effects of antioxidant vitamins

被引:158
作者
Cindrova-Davies, Tereza
Spasic-Boskovic, Olivera
Jauniaux, Eric
Charnock-Jones, D. Stephen
Burton, Graham J.
机构
[1] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England
[2] Univ Cambridge, Dept Obstet & Gynaecol, Cambridge CB2 3EG, England
[3] UCL Royal Free & Univ Coll, Acad Dept Obste & Gynaecol, London, England
基金
英国惠康基金;
关键词
D O I
10.2353/ajpath.2007.061035
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Preeclampsia is a potentially fatal complication of human pregnancy characterized by hypertension, proteinuria, and edema. Placental oxidative stress is a key element in the pathogenesis of the syndrome and results in the release of a cocktail of factors, including proinflammatory cytokines and apoptotic debris, that in turn cause activation of the maternal endothelium. The intermediary molecular mechanisms underlying this release are unknown, but they represent a potential target for therapeutic interventions. We examined activation of signaling pathways during hypoxia-reoxygenation of villous explants in vitro. Hypoxia-reoxygenation activated the p38 and stress-activated protein kinase mitogen-activated protein kinase (MAPK) and the nuclear factor-kappa B pathways. Downstream consequences included increased tissue concentrations and secretion of tumor necrosis factor-a and interleukin-1 beta, increased expression of cyclooxygenase-2, and increased apoptosis. Administration of vitamins C and E to explants blocked activation of the p38 and stress-activated protein kinase MAPK and nuclear factor-kappa B pathways. Vitamin administration or p38 pathway inhibition also reduced cyclooxygenase-2 expression, tumor necrosis factor-a and interleukin-1 beta secretion. and the levels of apoptosis. We conclude that oxidative stress is a potent inducer of placental synthesis and release of proinflammatory factors. Most of these effects are mediated through the p38 MAPK and nuclear factor-kappa B pathways and can be effectively blocked by vitamins C and E in vitro.
引用
收藏
页码:1511 / 1520
页数:10
相关论文
共 57 条
[1]   Human labour is associated with nuclear factor-κB activity which mediates cyclo-oxygenase-2 expression and is involved with the 'functional progesterone withdrawal' [J].
Allport, VC ;
Pieber, D ;
Slater, DM ;
Newton, R ;
White, JO ;
Bennett, PR .
MOLECULAR HUMAN REPRODUCTION, 2001, 7 (06) :581-586
[2]   Carbon monoxide inhibits hypoxia/reoxygenation-induced apoptosis and secondary necrosis in syncytiotrophoblast [J].
Bainbridge, Shannon A. ;
Belkacemi, Louiza ;
Dickinson, Michelle ;
Graham, Charles H. ;
Smith, Graeme N. .
AMERICAN JOURNAL OF PATHOLOGY, 2006, 169 (03) :774-783
[3]   Mechanism of vitamin E inhibition of cyclooxygenase activity in macrophages from old mice: Role of peroxynitrite [J].
Beharka, AA ;
Wu, DY ;
Serafini, M ;
Meydani, SN .
FREE RADICAL BIOLOGY AND MEDICINE, 2002, 32 (06) :503-511
[4]  
BERLANGIERI AJ, 1992, J AM COLL NUTR, V11, P131
[5]   ALPHA-TOCOPHEROL (VITAMIN-E) REGULATES VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION AND PROTEIN-KINASE-C ACTIVITY [J].
BOSCOBOINIK, D ;
SZEWCZYK, A ;
AZZI, A .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1991, 286 (01) :264-269
[6]  
BOSCOBOINIK D, 1991, J BIOL CHEM, V266, P6188
[7]   The myometrial junctional zone spiral arteries in normal and abnormal pregnancies - A review of the literature [J].
Brosens, JJ ;
Pijnenborg, R ;
Brosens, IA .
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2002, 187 (05) :1416-1423
[8]   Placental oxidative stress: From miscarriage to preeclampsia [J].
Burton, GJ ;
Jauniaux, E .
JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION, 2004, 11 (06) :342-352
[9]  
Burton GJ, 2003, Fetal Matern Med Rev, V14, P97, DOI 10.1017/S0965539503001049.
[10]   α-tocopherol inhibits the respiratory burst in human monocytes -: Attenuation of p47phox membrane translocation and phosphorylation [J].
Cachia, O ;
El Benna, J ;
Pedruzzi, E ;
Descomps, B ;
Gougerot-Pocidalo, MA ;
Leger, CL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (49) :32801-32805