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Park, Sung Ho
Laboratory of Molecular Immunology
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Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages

Author(s)
Park, Sung HoPark-Min, Kyung-HyunChen, JaniceHu, XiaoyuIvashkiv, Lionel B.
Issued Date
2011-07
DOI
10.1038/ni.2043
URI
https://scholarworks.unist.ac.kr/handle/201301/26385
Fulltext
https://www.nature.com/articles/ni.2043
Citation
NATURE IMMUNOLOGY, v.12, no.7, pp.607 - U158
Abstract
Endotoxin tolerance, a key mechanism for suppressing excessive inflammatory cytokine production, is induced by prior exposure of macrophages to Toll-like receptor (TLR) ligands. Induction of cross-tolerance to endotoxin by endogenous cytokines has not been investigated. Here we show that prior exposure to tumor necrosis factor (TNF) induced a tolerant state in macrophages, with less cytokine production after challenge with lipopolysaccharide (LPS) and protection from LPS-induced death. TNF-induced cross-tolerization was mediated by suppression of LPS-induced signaling and chromatin remodeling. TNF-induced cross-tolerance was dependent on the kinase GSK3, which suppressed chromatin accessibility and promoted rapid termination of signaling via the transcription factor NF-kappa B by augmenting negative feedback by the signaling inhibitors A20 and I kappa B alpha. Our results demonstrate an unexpected homeostatic function for TNF and a GSK3-mediated mechanism for the prevention of prolonged and excessive inflammation.
Publisher
NATURE PUBLISHING GROUP
ISSN
1529-2908
Keyword
NF-KAPPA-BGLYCOGEN-SYNTHASE KINASE-3-BETAGENE-SPECIFIC CONTROLRHEUMATOID-ARTHRITISTNF-ALPHAINFLAMMATORY RESPONSETEMPORAL CONTROLDENDRITIC CELLSI INTERFERONEXPRESSION

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