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Xiong, Y, Qiu, F, Piao, W, Song, C, Wahl, LM and Medvedev, AE (2011) Endotoxin tolerance impairs IL-1 receptor-associated kinase (IRAK) 4 and TGF-beta-activated kinase 1 activation, K63-linked polyubiquitination and assembly of IRAK1, TNF receptor-associated factor 6, and IkappaB kinase gamma and increases A20 expression. J. Biol. Chem. 286:7905-16


Endotoxin tolerance reprograms Toll-like receptor 4 responses by impairing LPS-elicited production of pro-inflammatory cytokines without inhibiting expression of anti-inflammatory or anti-microbial mediators. In septic patients, Toll-like receptor tolerance is thought to underlie decreased pro-inflammatory cytokine expression in response to LPS and increased incidence of microbial infections. The impact of endotoxin tolerance on recruitment, post-translational modifications and signalosome assembly of IL-1 receptor-associated kinase (IRAK) 4, IRAK1, TNF receptor-associated factor (TRAF) 6, TGF-β-activated kinase (TAK) 1, and IκB kinase (IKK) γ is largely unknown. We report that endotoxin tolerization of THP1 cells and human monocytes impairs LPS-mediated receptor recruitment and activation of IRAK4, ablates K63-linked polyubiquitination of IRAK1 and TRAF6, compromises assembly of IRAK1-TRAF6 and IRAK1-IKKγ platforms, and inhibits TAK1 activation. Deficiencies in these signaling events in LPS-tolerant cells coincided with increased expression of A20, an essential deubiquitination enzyme, and sustained A20-IRAK1 associations. Overexpression of A20 inhibited LPS-induced activation of NF-κB and ablated NF-κB reporter activation driven by ectopic expression of MyD88, IRAK1, IRAK2, TRAF6, and TAK1/TAB1, while not affecting the responses induced by IKKβ and p65. A20 shRNA knockdown abolished LPS tolerization of THP1 cells, mechanistically linking A20 and endotoxin tolerance. Thus, deficient LPS-induced activation of IRAK4 and TAK1, K63-linked polyubiquitination of IRAK1 and TRAF6, and disrupted IRAK1-TRAF6 and IRAK1-IKKγ assembly associated with increased A20 expression and A20-IRAK1 interactions are new determinants of endotoxin tolerance.


PubMed PMC3048677 Online version:10.1074/jbc.M110.182873


Cell Line; Drug Resistance/drug effects; Gene Expression Regulation/drug effects; Humans; I-kappa B Kinase/genetics; I-kappa B Kinase/metabolism; Interleukin-1 Receptor-Associated Kinases/genetics; Interleukin-1 Receptor-Associated Kinases/metabolism; Intracellular Signaling Peptides and Proteins/genetics; Lipopolysaccharides/pharmacology; MAP Kinase Kinase Kinases/genetics; MAP Kinase Kinase Kinases/metabolism; Monocytes/metabolism; Myeloid Differentiation Factor 88/genetics; Myeloid Differentiation Factor 88/metabolism; Nuclear Proteins/biosynthesis; Nuclear Proteins/genetics; TNF Receptor-Associated Factor 6/genetics; TNF Receptor-Associated Factor 6/metabolism; Ubiquitination/drug effects