title: Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages.
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-κB by augmenting negative feedback by the signaling inhibitors A20 and IκBα. Our results demonstrate an unexpected homeostatic function for TNF and a GSK3-mediated mechanism for the prevention of prolonged and excessive inflammation.
authors: Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
authors: Sung Ho
authors: SH
authors: Park
authors: Kyung-Hyun
authors: KH
authors: Park-Min
authors: Janice
authors: J
authors: Chen
authors: Xiaoyu
authors: X
authors: Hu
authors: Lionel B
authors: LB
authors: Ivashkiv
references: J Cell Sci. 2003 Apr 1;116(Pt 7):1175-86
references: 12615961
references: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13806-11
references: 9811882
references: Clin Immunol. 2009 Jan;130(1):7-15
references: 18964303
references: J Biol Chem. 2004 Sep 17;279(38):39541-54
references: 15252041
references: Immunol Rev. 1999 Jun;169:175-94
references: 10450517
references: J Immunol. 2001 Jun 15;166(12):7023-32
references: 11390446
references: Immunol Rev. 2009 Jan;227(1):248-63
references: 19120489
references: Shock. 2003 Jun;19(6):553-8
references: 12785011
references: Nat Rev Immunol. 2005 Jun;5(6):446-58
references: 15928677
references: Arthritis Rheum. 2010 Jun;62(6):1608-19
references: 20155834
references: Nat Immunol. 2005 May;6(5):439-45
references: 15843800
references: Nat Immunol. 2001 Jan;2(1):51-7
references: 11135578
references: Nature. 2000 Jul 6;406(6791):86-90
references: 10894547
references: Nature. 2007 Jun 21;447(7147):972-8
references: 17538624
references: Nat Immunol. 2004 Oct;5(10):1052-60
references: 15334086
references: Nat Genet. 2010 Jun;42(6):508-14
references: 20453842
references: Sci Signal. 2009 Feb 24;2(59):ra8
references: 19244213
references: Blood. 2007 Feb 15;109(4):1584-92
references: 17032918
references: Cell. 2009 Apr 3;137(1):47-59
references: 19345186
references: Genes Dev. 2006 Feb 1;20(3):282-96
references: 16452502
references: Arthritis Rheum. 2009 Feb;60(2):408-18
references: 19180511
references: Int J Dermatol. 2008 Nov;47(11):1101-11
references: 18986438
references: Genes Dev. 2008 Aug 1;22(15):2093-101
references: 18676814
references: J Endotoxin Res. 2007;13(1):39-52
references: 17621545
references: J Cell Biochem. 2008 May 1;104(1):329-38
references: 18027881
references: Immunity. 2006 May;24(5):563-74
references: 16713974
references: Immunity. 2006 Sep;25(3):383-92
references: 16979570
references: Anesth Analg. 2001 May;92(5):1322-6
references: 11323370
references: Nat Immunol. 2002 Jan;3(1):69-75
references: 11743587
references: Nat Immunol. 2010 May;11(5):373-84
references: 20404851
references: J Exp Med. 2001 Feb 19;193(4):427-34
references: 11181695
references: Pediatr Surg Int. 2006 Jan;22(1):24-30
references: 16292653
references: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19438-43
references: 20974955
references: J Biol Chem. 2004 Nov 26;279(48):49571-4
references: 15465828
references: Cell. 2010 Mar 19;140(6):833-44
references: 20303874
references: Science. 2005 Sep 16;309(5742):1857-61
references: 16166517
references: Nat Rev Immunol. 2003 Sep;3(9):745-56
references: 12949498
references: Nat Immunol. 2008 Apr;9(4):378-87
references: 18345002
references: Cell. 2010 Mar 19;140(6):871-82
references: 20303877
references: J Biol Chem. 2006 Jun 23;281(25):16985-16990
references: 16601113
references: Trends Immunol. 2009 Oct;30(10):475-87
references: 19781994
references: Trends Immunol. 2010 Jan;31(1):24-31
references: 19836308
references: J Immunol. 2005 Oct 15;175(8):5024-33
references: 16210605
references: Mol Cell Biol. 2008 Oct;28(20):6314-28
references: 18694957
references: Nat Genet. 2007 Dec;39(12):1477-82
references: 17982456
references: Arthritis Rheum. 2003 Aug;48(8):2092-6
references: 12905460
references: Mol Cell Biol. 2005 Oct;25(19):8444-55
references: 16166627
references: Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8093-8
references: 9223320
references: Nat Immunol. 2005 Aug;6(8):777-84
references: 16007092
references: Cell. 2008 Feb 8;132(3):344-62
references: 18267068