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11 June 2018 Oxidative stress-induced TGF-beta/TAB1-mediated p38MAPK activation in human amnion epithelial cells
Lauren Richardson, Christopher Luke Dixon, Leopoldo Aguilera-Aguirre, Ramkumar Menon
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Term and preterm parturition are associated with oxidative stress (OS)-induced p38 mitogenactivated protein kinase (p38MAPK)-mediated fetal tissue (amniochorion) senescence. p38MAPK activation is a complex cell- and stimulant-dependent process. Two independent pathways of OS-induced p38MAPK activation were investigated in amnion epithelial cells (AECs) in response to cigarette smoke extract (CSE: a validated OS inducer in fetal cells): (1) the OS-mediated oxidation of apoptosis signal-regulating kinase (ASK)-1 bound Thioredoxin (Trx[SH]2) dissociates this complex, creating free and activated ASK1-signalosome and (2) transforming growth factor-mediated activation of (TGF)-beta-activated kinase (TAK)1 and TGF-beta-activated kinase 1-binding protein (TAB)1. AECs isolated from normal term, not-in-labor fetal membranes increased p38MAPK in response to CSE and downregulated it in response to antioxidant N-acetylcysteine. In AECs, both Trx and ASK1 were localized; however, they remained dissociated and not complexed, regardless of conditions. Silencing either ASK1 or its downstream effectors (MKK3/6) did not affect OS-induced p38MAPK activation. Conversely, OS increased TGF-beta's release from AECs and increased phosphorylation of both p38MAPK and TAB1. Silencing of TAB1, but not TAK1, prevented p38MAPK activation, which is indicative of TAB1-mediated autophosphorylation of p38MAPK, an activation mechanism seldom seen. OS-induced p38MAPK activation in AECs is ASK1-Trx signalosome-independent and is mediated by the TGF-beta pathway. This knowledge will help to design strategies to reduce p38MAPK activation-associated pregnancy risks.

Summary Sentence

Oxidative stress-induced p38MAPK activation at term is dependent on the TGF-beta—TAB1 pathway.

© The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail:
Lauren Richardson, Christopher Luke Dixon, Leopoldo Aguilera-Aguirre, and Ramkumar Menon "Oxidative stress-induced TGF-beta/TAB1-mediated p38MAPK activation in human amnion epithelial cells," Biology of Reproduction 99(5), 1100-1112, (11 June 2018).
Received: 23 February 2018; Accepted: 7 June 2018; Published: 11 June 2018
Cell culture
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