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Oxidative Stress-Induced TGF-beta/TAB1-mediated p38MAPK activation in human amnion epithelial cells.

Term and preterm parturition are associated with oxidative stress (OS)-induced p38 mitogen-activated protein kinase (MAPK)-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-signaling 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.

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