Letter | Published:

Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6

Nature volume 525, pages 389393 (17 September 2015) | Download Citation


Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status1. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members2, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered3. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IκBζ, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IκBζ at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.

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Gene Expression Omnibus

Data deposits

The deep sequencing data have been deposited in the Gene Expression Omnibus under accession number GSE69256.


  1. 1.

    & Chromatin modifiers and remodellers: regulators of cellular differentiation. Nature Rev. Genet. 15, 93–106 (2014)

  2. 2.

    & TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472–479 (2013)

  3. 3.

    , & TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nature Rev. Mol. Cell Biol. 14, 341–356 (2013)

  4. 4.

    et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009)

  5. 5.

    et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839–843 (2010)

  6. 6.

    et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295, 338–342 (2002)

  7. 7.

    et al. Involvement of innate immunity in the development of inflammatory and autoimmune diseases. Ann. NY Acad. Sci. 1051, 787–798 (2005)

  8. 8.

    Cytokines in inflammatory bowel disease. Nature Rev. Immunol. 14, 329–342 (2014)

  9. 9.

    et al. The methylcytosine dioxygenase tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 42, 613–626 (2015)

  10. 10.

    et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 430, 218–222 (2004)

  11. 11.

    et al. Class-specific regulation of pro-inflammatory genes by MyD88 pathways and IκBζ. J. Biol. Chem. 283, 12468–12477 (2008)

  12. 12.

    et al. IκBζ is a transcriptional key regulator of CCL2/MCP-1. J. Immunol. 190, 4812–4820 (2013)

  13. 13.

    et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–348 (2011)

  14. 14.

    , , , & TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561–564 (2013)

  15. 15.

    et al. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. 32, 645–655 (2013)

  16. 16.

    , & Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007)

  17. 17.

    et al. Synergistic activation of inflammatory cytokine genes by interferon-gamma-induced chromatin remodeling and toll-like receptor signaling. Immunity 39, 454–469 (2013)

  18. 18.

    et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010)

  19. 19.

    , , & Inhibition of histone deacetylase class I but not class II is critical for the sensitization of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res. 66, 6785–6792 (2006)

  20. 20.

    et al. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc. Natl Acad. Sci. USA 109, E2865–E2874 (2012)

  21. 21.

    et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011)

  22. 22.

    et al. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep 9, 1841–1855 (2014)

  23. 23.

    et al. Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO. Nature Immunol. 15, 612–622 (2014)

  24. 24.

    & IL-6 as a keystone cytokine in health and disease. Nature Immunol. 16, 448–457 (2015)

  25. 25.

    et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nature Immunol. 12, 861–869 (2011)

  26. 26.

    et al. Histone lysine methyltransferase Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing Tollip. J. Immunol. 194, 2838–2846 (2015)

  27. 27.

    et al. Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell 152, 467–478 (2013)

  28. 28.

    et al. Histone methyltransferase Ash1l suppresses interleukin-6 production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20. Immunity 39, 470–481 (2013)

  29. 29.

    et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129–1133 (2010)

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This work was supported by the National Key Basic Research Program of China (2013CB530503) and the National Natural Science Foundation of China (31200654, 31390431, 81230074, 81123006).

Author information

Author notes

    • Qian Zhang
    • , Kai Zhao
    • , Qicong Shen
    •  & Yanmei Han

    These authors contributed equally to this work.


  1. National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China

    • Qian Zhang
    • , Kai Zhao
    • , Xia Li
    • , Dezhi Zhao
    • , Chunmei Wang
    • , Wei Ge
    •  & Xuetao Cao
  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China

    • Qian Zhang
    • , Qicong Shen
    • , Yanmei Han
    • , Yan Gu
    • , Yiqi Liu
    • , Xiang Zhang
    • , Xiaoping Su
    • , Juan Liu
    • , Nan Li
    •  & Xuetao Cao
  3. Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer, New York, New York 10016, USA

    • Ross L. Levine


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Q.Z., K.Z., Q.S. and Y.H. performed the experiments, analysed the data and contributed equally for the whole study. Y.G., X.L., D.Z., Y.L., C.W., X.Z., X.S., J.L., W.G. and N.L. provided reagents and performed experiments; RL.L. provided Tet2 KO mice. X.C. and Q.Z. analysed the data and wrote the manuscript. X.C. designed and supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Xuetao Cao.

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