Nuclear factor-kappa B, 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.
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-kappaB pathways. Downstream consequences included increased tissue concentrations and secretion of tumor necrosis factor-alpha 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-kappaB pathways. Vitamin administration or p38 pathway inhibition also reduced cyclooxygenase-2 expression, tumor necrosis factor-alpha 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-kappaB pathways and can be effectively blocked by vitamins C and E in vitro.
Cindrova-Davies
Tereza
T
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Spasic-Boskovic
Olivera
O
Jauniaux
Eric
E
Charnock-Jones
D Stephen
DS
Burton
Graham J
GJ
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology; D015153:Blotting, Western; D002824:Chorionic Villi / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011225:Pre-Eclampsia / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014810:Vitamin E / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D014810:Vitamin E; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid