Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages

Park SH, et al., Nat Immunol. 2011. 12:607-615.

Speaker：Yu-Chang Chang (張育菖)                                       Time：13:10~14:00, Sep. 21, 2011

Commentator：Chiou-Feng Lin, Ph.D. (林秋烽 博士)  Place：Room 601

Abstract:

Prior exposure of immune cells like macrophages to low amounts of endotoxin causes them to be more unresponsive to produce cytokines after further challenge with endotoxin, which phenomenon is called “endotoxin tolerance”¹. The induction of cross-tolerance to endotoxin by endogenous cytokines has not been investigated. Tumor necrosis factor (TNF) is a potent proinflammatory cytokine, and its predominantly activating role in innate immunity and host defense is well described. However, anti-inflammatory effects of TNF have also been reported^2,3, but the mechanism remains unclear. In this study, the authors investigated whether TNF can induce an endotoxin tolerance-like state, that is, selective hyporesponsiveness and diminished inflammatory response after secondary Toll-like receptor (TLR) challenge. They demonstrated that TNF could induce cross-tolerance to endotoxin both in human and mouse macrophages at the levels of cytokine production and gene expression, and that TNF could also induce endotoxin tolerance to attenuate inflammatory responses and confer protection after secondary challenge with lipopolysaccharidein mice. To the mechanism of TNF-induced cross-tolerance, it was associated with decreased TLR4 signaling and chromatin remodeling, and was mediated by GSK3 kinase. GSK3 kinase suppressed chromatin accessibility and terminated TLR4 signaling via transcription factor NF-kB by increasing negative feedback signaling inhibitors A20 and IkBa. In conclusion, the authors identify an unexpected homeostatic function of TNF and demonstrate the role of GSK3 in controlling TNF-induced cross-tolerance to endotoxin for the prevention of prolonged and excessive inflammation.

References:

1.      Biswas SK. and Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009 30:475-487

2.      Blüml S, et al., Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritis. Arthritis Rheum. 2010 62:1608-1619.

3.      Nathan C. and Ding A. Nonresolving inflammation. Cell. 2010 140:871-882.