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

Nature Immunology volume 12, pages 607–615 (2011)Cite this article

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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.

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Figure 1: Pretreatment with TNF suppresses the induction of proinflammatory cytokines on secondary challenge by LPS.
Figure 2: TNF suppresses cytokine production in vivo and protects mice from LPS-induced death.
Figure 3: TNF suppresses TLR4 signaling and induces A20 expression.
Figure 4: GSK3 mediates TNF-induced cross-tolerance.
Figure 5: GSK3 regulates the kinetics of IκBα expression and repression of NF-κB signaling after induction in LPS-stimulated, TNF-tolerized macrophages.
Figure 6: TNF-induced A20 expression is mediated by GSK3.
Figure 7: TNF and GSK3 regulate the accessibility of chromatin at the IL6 promoter.

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Acknowledgements

We thank G.D. Kalliolias and A. Yarilina for discussions and J. Woodgett (University of Toronto) for mice with loxP-flanked alleles encoding GSK3β. Supported by the National Institutes of Health (L.B.I.).

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Authors and Affiliations

  1. Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA

    Sung Ho Park & Lionel B Ivashkiv

  2. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA

    Sung Ho Park, Kyung-Hyun Park-Min, Janice Chen, Xiaoyu Hu & Lionel B Ivashkiv

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  1. Sung Ho Park
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Contributions

S.H.P. designed and did experiments and wrote the manuscript; K.-H.P.-M. contributed to the signaling experiments; J.C. contributed to the restriction-enzyme accessibility experiments; X.H. contributed to the in vivo experiments; and L.B.I. designed and supervised the research and wrote the manuscript.

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Correspondence to Lionel B Ivashkiv.

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Park, S., Park-Min, KH., Chen, J. et al. Tumor necrosis factor induces GSK3 kinase–mediated cross-tolerance to endotoxin in macrophages. Nat Immunol 12, 607–615 (2011). https://doi.org/10.1038/ni.2043

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