國家衛生研究院 NHRI:Item 3990099045/10441

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Title:	Cytokine-induced autophagy promotes sustained expression of VCAM-1 and a subset of pro-inflammatory genes with similar promoter binding motifs
Authors:	Chu, L;Hsueh, Y;Wu, KK
Contributors:	Institute of Cellular and Systems Medicine
Abstract:	Pro‐inflammatory cytokines induce the expression of adhesive molecules such as VCAM‐1 and ICAM‐1 as well as chemokines and cytokines in human endothelial cells by activation of NF‐κB. However, it is unclear whether autophagy is involved. We tested the hypothesis that inflammatory cytokines induce autophagy which regulates the expression of a subset of pro‐inflammatory mediators. To test this hypothesis we treated human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor α (TNFα), interleukin‐1β (IL‐1β) or rapamycin and analyzed LC3B‐II and Beclin‐1. TNFα and IL‐1β increased LC3B‐II and Beclin‐1 to an extent comparable to rapamycin. TNFα and IL‐1β stimulated VCAM‐1 and ICAM‐1 expression in a time‐dependent manner whereas rapamycin did not. Inhibition of autophagy with 3‐methyladenine (3‐MA) resulted in suppression of VCAM‐1 expression at 24h but not 6h after addition of TNFα or IL‐1β. 3‐MA did not inhibit TNFα or IL‐1β‐induced ICAM‐1 at 6h or 24h. We suspected that the differential inhibition of VCAM‐1 vs ICAM‐1 at 24h may be due to selective degradation of IκB isoforms by autophagy. To address this, we analyzed IκBα, β and ε in HUVECs treated with TNFα or IL‐1β with or without 3‐MA. TNFα and IL‐1β induced a similar bi‐phasic degradation of IκBα: an immediate early phase and a late‐phase, while they induced a monophasic degradation of IκBβ and IκBε. Pretreatment with 3‐MA selectively abrogated the late‐phase IκBα degradation without an effect on IκBβ or IκBε degradation. To determine whether autophagy regulates cytokines and chemokines, we evaluated the effect of 3‐MA on TNFα or IL‐1β‐induced cytokines/chemokines using an antibody array which contains 80 cytokines, chemokines and growth factors. Of the 9 cytokines/chemokines stimulated by TNFα and/or IL‐1β, 3‐MA inhibited IP‐10 selectively. Interestingly, IP‐10 shares with VCAM‐1 similar NF‐κB binding motifs in the promoter region. These findings suggest that cytokine‐induced autophagy selectively promotes the sustained expression of VCAM‐1, IP‐10 and a subset of genes with similar binding motifs by degrading late‐phase IκBα.
Date:	2016-12
Relation:	Molecular Biology of the Cell. 2016 Dec;27:Meeting Abstract P1178.
Link to:	http://www.ascb.org/wp-content/uploads/2016/04/2016ASCBMeeting-PosterAbstracts.pdf
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1059-1524&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000396047100181
Appears in Collections:	[Kenneth Kun-Yu Wu] Conference Papers/Meeting Abstract

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