| First Author | Park SH | Year | 2011 |
| Journal | Nat Immunol | Volume | 12 |
| Issue | 7 | Pages | 607-15 |
| PubMed ID | 21602809 | Mgi Jnum | J:174318 |
| Mgi Id | MGI:5056256 | Doi | 10.1038/ni.2043 |
| Citation | Park SH, et al. (2011) Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages. Nat Immunol 12(7):607-15 |
| abstractText | 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-kappaB by augmenting negative feedback by the signaling inhibitors A20 and IkappaBalpha. Our results demonstrate an unexpected homeostatic function for TNF and a GSK3-mediated mechanism for the prevention of prolonged and excessive inflammation. |
