Gene-specific control of inflammation by TLR-induced chromatin modifications

A Corrigendum to this article was published on 03 January 2008


Toll-like receptors (TLRs) induce a multi-component inflammatory response that must be tightly regulated to avoid tissue damage. Most known regulatory mechanisms target TLR signalling pathways and thus broadly inhibit multiple aspects of the inflammatory response. Given the functional diversity of TLR-induced genes, we proposed that additional, gene-specific regulatory mechanisms exist to allow individual aspects of the TLR-induced response to be differentially regulated. Using an in vitro system of lipopolysaccharide tolerance in murine macrophages, we show that TLR-induced genes fall into two categories on the basis of their functions and regulatory requirements. We demonstrate that representatives from the two classes acquire distinct patterns of TLR-induced chromatin modifications. These gene-specific chromatin modifications are associated with transient silencing of one class of genes, which includes pro-inflammatory mediators, and priming of the second class, which includes antimicrobial effectors. These findings illustrate an adaptive response in macrophages and reveal component-specific regulation of inflammation.

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Figure 1: Identification of class T and class NT genes.
Figure 2: Histone modifications are differentially regulated at class T and NT promoters.
Figure 3: Chromatin remodelling is differentially regulated at class T and NT promoters.
Figure 4: Transcription of new genes contributes to the tolerant signature.
Figure 5: Class NT genes have different transcriptional requirements in naive and tolerant macrophages.
Figure 6: Model for gene-specific regulation of class T and NT genes.


  1. 1

    Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003)

    CAS  Article  Google Scholar 

  3. 3

    Nieuwdorp, M., Stroes, E. S., Meijers, J. C. & Buller, H. Hypercoagulability in the metabolic syndrome. Curr. Opin. Pharmacol. 5, 155–159 (2005)

    CAS  Article  Google Scholar 

  4. 4

    Karin, M., Lawrence, T. & Nizet, V. Innate immunity gone awry: Linking microbial infections to chronic inflammation and cancer. Cell 124, 823–835 (2006)

    CAS  Article  Google Scholar 

  5. 5

    Liew, F. Y., Xu, D., Brint, E. K. & O’Neill, L. A. Negative regulation of toll-like receptor-mediated immune responses. Nature Rev. Immunol. 5, 446–458 (2005)

    CAS  Article  Google Scholar 

  6. 6

    Beeson, P. B. Tolerance to bacterial pyrogens I: Factors influencing its development. J. Exp. Med. 86, 29–38 (1947)

    CAS  Article  Google Scholar 

  7. 7

    Beeson, P. B. Tolerance to bacterial pyrogens II: Role of the reticulo-endothelial system. J. Exp. Med. 86, 39–44 (1947)

    CAS  Article  Google Scholar 

  8. 8

    West, M. A. & Heagy, W. Endotoxin tolerance: A review. Crit. Care Med. 30, S64–S73 (2002)

    CAS  Article  Google Scholar 

  9. 9

    Cavaillon, J. M. & Adib-Conquy, M. Bench to bedside review: Endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit. Care 10, 1–8 (2006)

    Article  Google Scholar 

  10. 10

    Dobrovolskaia, M. A. & Vogel, S. N. Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect. 4, 903–914 (2002)

    CAS  Article  Google Scholar 

  11. 11

    Fujihara, M. et al. Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex. Pharmacol. Ther. 100, 171–194 (2003)

    CAS  Article  Google Scholar 

  12. 12

    Medvedev, A. E., Kopydlowski, K. M. & Vogel, S. N. Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: Dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression. J. Immunol. 164, 5564–5574 (2000)

    CAS  Article  Google Scholar 

  13. 13

    Medvedev, A. E., Lentschat, A., Wahl, L. M., Golenbock, D. T. & Vogel, S. N. Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J. Immunol. 169, 5209–5216 (2002)

    Article  Google Scholar 

  14. 14

    Fujihara, M. et al. Lipopolysaccharide-triggered desensitization of TNF-α mRNA expression involves lack of phosphorylation of IκBα in a murine macrophage-like cell line, P388D1. J. Leukoc. Biol. 68, 267–276 (2000)

    CAS  PubMed  Google Scholar 

  15. 15

    Dobrovolskaia, M. A. et al. Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: Effects of TLR “homotolerance” versus “heterotolerance” on NF-κ B signaling pathway components. J. Immunol. 170, 508–519 (2003)

    CAS  Article  Google Scholar 

  16. 16

    Huang, Q. et al. The plasticity of dendritic cell responses to pathogens and their components. Science 294, 870–875 (2001)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Ogawa, S. et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122, 707–721 (2005)

    CAS  Article  Google Scholar 

  18. 18

    De Bosscher, K., Vanden Berghe, W. & Haegeman, G. The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: Molecular mechanisms for gene repression. Endocr. Rev. 24, 488–522 (2003)

    CAS  Article  Google Scholar 

  19. 19

    Narlikar, G. J., Fan, H. Y. & Kingston, R. E. Cooperation between complexes that regulate chromatin structure and transcription. Cell 108, 475–487 (2002)

    CAS  Article  Google Scholar 

  20. 20

    Chi, T. A BAF-centred view of the immune system. Nature Rev. Immunol. 4, 965–977 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001)

    CAS  Article  Google Scholar 

  23. 23

    Kurdistani, S. K. & Grunstein, M. Histone acetylation and deacetylation in yeast. Nature Rev. Mol. Cell Biol. 4, 276–284 (2003)

    CAS  Article  Google Scholar 

  24. 24

    Leoni, F. et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol. Med. 11, 1–15 (2005)

    CAS  Article  Google Scholar 

  25. 25

    Nusinzon, I. & Horvath, C. M. Unexpected roles for deacetylation in interferon- and cytokine-induced transcription. J. Interferon Cytokine Res. 25, 745–748 (2005)

    CAS  Article  Google Scholar 

  26. 26

    Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Schneider, R. et al. Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nature Cell Biol. 6, 73–77 (2004)

    CAS  Article  Google Scholar 

  28. 28

    Pokholok, D. K. et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122, 517–527 (2005)

    CAS  Article  Google Scholar 

  29. 29

    Bernstein, B. E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005)

    CAS  Article  Google Scholar 

  30. 30

    Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005)

    ADS  CAS  Article  Google Scholar 

  31. 31

    Ramirez-Carrozzi, V. R. et al. Selective and antagonistic functions of SWI/SNF and Mi-2β nucleosome remodeling complexes during an inflammatory response. Genes Dev. 20, 282–296 (2006)

    CAS  Article  Google Scholar 

  32. 32

    Kaufmann, A., Gemsa, D. & Sprenger, H. Differential desensitization of lipopolysaccharide-inducible chemokine gene expression in human monocytes and macrophages. Eur. J. Immunol. 30, 1562–1567 (2000)

    CAS  Article  Google Scholar 

  33. 33

    Learn, C. A., Mizel, S. B. & McCall, C. E. mRNA and protein stability regulate the differential expression of pro- and anti-inflammatory genes in endotoxin-tolerant THP-1 cells. J. Biol. Chem. 275, 12185–12193 (2000)

    CAS  Article  Google Scholar 

  34. 34

    Henricson, B. E., Manthey, C. L., Perera, P. Y., Hamilton, T. A. & Vogel, S. N. Dissociation of lipopolysaccharide (LPS)-inducible gene expression in murine macrophages pretreated with smooth LPS versus monophosphoryl lipid A. Infect. Immun. 61, 2325–2333 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Shnyra, A., Brewington, R., Alipio, A., Amura, C. & Morrison, D. C. Reprogramming of lipopolysaccharide-primed macrophages is controlled by a counterbalanced production of IL-10 and IL-12. J. Immunol. 160, 3729–3736 (1998)

    CAS  PubMed  Google Scholar 

  36. 36

    Flohe, S. et al. Endotoxin tolerance in rats: Expression of TNF-α, IL-6, IL-10, VCAM-1 and HSP 70 in lung and liver during endotoxin shock. Cytokine 11, 796–804 (1999)

    CAS  Article  Google Scholar 

  37. 37

    Smale, S. T. The establishment and maintenance of lymphocyte identity through gene silencing. Nature Immunol. 4, 607–615 (2003)

    CAS  Article  Google Scholar 

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We thank S. Smale, T. Chi, M. Wan and R. Rutishauser for discussions, gifts of reagents, and technical assistance. S.L.F. is supported by the UNCF-Merck Graduate Science Research Dissertation Fellowship and by the NIH. D.C.H. is supported by the NSF and the graduate programme at Yale University. R.M. is supported by funding from the Howard Hughes Medical Institute, and the NIH.

All microarray data are available from the Gene Expression Omnibus database ( under accession code GSE7348.

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Correspondence to Ruslan Medzhitov.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-5 and Supplementary Table 2. Supplementary Figure 1 shows pie chart representations of 50 of the top 100 genes from the class T and NT categories divided into functional groups. Supplementary Figure 2 shows more gene examples from Figure 1f, 1g, and 2b. Supplementary Figure 3 shows class NT gene induction is not due to increased mRNA stability, increased sensitivity to LPS, or positive feedback of secreted factors. Supplementary Figure 4 shows class T and NT genes are induced by the same signaling pathways in naive and tolerant macrophages, despite reduced signalling in tolerant macrophages. Supplementary Figure 5 shows reversal of suppression of class T genes following TSA, Pargyline, or DRB treatment is not due to changes in signalling in tolerant macrophages. Supplementary Table 2 shows individual gene names listed for genes represented in the pie charts in Supplementary Figure 1. (PDF 1557 kb)

Supplementary Table 1

This file contains Supplementary Table 1. The table contains expression data for genes differentially regulated in naïve and tolerant macrophages stimulated with LPS. Microarray analysis and gene selection was performed as described in Supplementary Methods. a) Class T genes. b) Class NT genes. (XLS 141 kb)

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Foster, S., Hargreaves, D. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

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