Divergent effects of p47(phox) phosphorylation at S303-4 or S379 on tumor necrosis factor-α signaling via TRAF4 and MAPK in endothelial cells.
نویسندگان
چکیده
OBJECTIVE To define the mechanism of p47(phox) phosphorylation in regulating endothelial cell response to tumor necrosis factor-α (TNFα) stimulation. METHODS AND RESULTS We replaced 11 serines (303-4, 310, 315, 320, 328, 345, 348, 359, 370, and 379) with alanines and investigated their effects on TNFα (100 U/mL, 30 minutes)-induced acute O(2)(.-) production and mitogen-activated protein kinase phosphorylation in endothelial cells. Seven constructs, S303-4A (double), S310A, S315A, S328A, S345A, S370A, and S379A, significantly reduced the O(2)(.-) production, and 4 of them (S328A, S345A, S370A, and S379A) also inhibited TNFα-induced extracellular-signal-regulated kinase (ERK) 1/2 phosphorylation. Blocking the phosphorylation of S303-4 and S379 inhibited most effectively TNFα-induced O(2)(.-) production. However, phosphorylation of S303-4 was not required for TNFα-induced p47(phox) membrane translocation and binding to TNF receptor-associated factor 4, ERK1/2 activation, and subsequent vascular cell adhesion molecule-1 expression. Knockout of p47(phox) or knockdown of TNF receptor-associated factor 4 using siRNA abolished TNFα-induced ERK1/2 phosphorylation, and inhibition of ERK1/2 activation significantly reduced the TNFα-induced vascular cell adhesion molecule-1 expression. CONCLUSIONS Phosphorylation of p47(phox) at different serine sites plays distinct roles in endothelial cell response to TNFα stimulation. Double serine (S303-4) phosphorylation is crucial for acute O(2)(.-) production, but is not involved in TNFα signaling through TNF receptor-associated factor 4 and ERK1/2. p47(phox) requires serine phosphorylation at distinct sites to support specific signaling events in response to TNFα.
منابع مشابه
divergent effects of p47phox Phosphorylation at s303-4 or s379 on Tumor Necrosis Factor-a signaling via TrAF4 and MAPK in endothelial cells
متن کامل
Subcommittee on behalf of the American Heart Association Statistics Committee and Stroke Statistics
on behalf of the American Heart Association Statistics Committee and Stroke Statistics Lei Teng, Lampson M. Fan, Daniel Meijles and Jian-Mei Li Signaling via TRAF4 and MAPK in Endothelial Cells α Phosphorylation at S303-4 or S379 on Tumor Necrosis Factorphox Divergent Effects of p47 Print ISSN: 1079-5642. Online ISSN: 1524-4636 Copyright © 2012 American Heart Association, Inc. All rights reserv...
متن کاملVGB3 Induces Apoptosis by Inhibiting Phosphorylation of NF-κB p65 at Serine 536 in the Human Umbilical Vein Endothelial Cells
Background and objectives: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibition results in an increase in apoptosis. It has been demonstrated that NF-κB subunit p65 phosphorylation at the IκB kinase phosphorylation site serine 536 (Ser536) is essential for the NF-κB nuclear translocation and activation. Therefore, NF-κB can be downregulated by suppressing its phosph...
متن کاملTNF-α-Induced cPLA2 Expression via NADPH Oxidase/Reactive Oxygen Species-Dependent NF-κB Cascade on Human Pulmonary Alveolar Epithelial Cells
Tumor necrosis factor-α (TNF-α) triggers activation of cytosolic phospholipase A2 (cPLA2) and then enhancing the synthesis of prostaglandin (PG) in inflammatory diseases. However, the detailed mechanisms of TNF-α induced cPLA2 expression were not fully defined in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that TNF-α-stimulated increases in cPLA2 mRNA (5.2 folds) and protein ...
متن کاملتمایز سلول‌های دندریتیک مشتق از مونوسیت بر روی لایه‌ای از سلول‌های اندوتلیال به‌عنوان لایه تغذیه‌کننده
Background: The innate and adaptive immune responses are dependent on the migration of leukocytes across endothelial cells. Dendritic cells (DCs) play an important role in the initiation of cellular immune responses during their migration from tissues into the lymph nodes where they interact with endothelial cells of lymphatic vessels. We investigated the effect...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Arteriosclerosis, thrombosis, and vascular biology
دوره 32 6 شماره
صفحات -
تاریخ انتشار 2012