Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

IL-37 is a fundamental inhibitor of innate immunity

Abstract

The function of interleukin 37 (IL-37; formerly IL-1 family member 7) has remained elusive. Expression of IL-37 in macrophages or epithelial cells almost completely suppressed production of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. Anti-inflammatory cytokines were unaffected. Mice with transgenic expression of IL-37 were protected from lipopolysaccharide-induced shock, and showed markedly improved lung and kidney function and reduced liver damage after treatment with lipopolysaccharide. Transgenic mice had lower concentrations of circulating and tissue cytokines (72–95% less) than wild-type mice and showed less dendritic cell activation. IL-37 interacted intracellularly with Smad3 and IL-37-expressing cells and transgenic mice showed less cytokine suppression when endogenous Smad3 was depleted. IL-37 thus emerges as a natural suppressor of innate inflammatory and immune responses.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Production and silencing of endogenous IL-37 in human PBMCs.
Figure 2: Effect of TLR-induced IL-37b on cytokine production in RAW cells.
Figure 3: Cytokine production in THP-1 and A549 cells transfected with the pIRES-IL-37b plasmid or mock-transfected with pIRES lacking IL-37b.
Figure 4: Smad3 and IL-37.
Figure 5: Amelioration of endotoxic shock in mice transgenic for IL-37b.
Figure 6: Production of LPS-induced cytokines in IL-37tg mice.
Figure 7: Cytokines and DC activation in IL-37tg and neg-WT spleens and whole blood.
Figure 8: Silencing of Smad3 reduces the activity of IL-37 in vivo.

Similar content being viewed by others

References

  1. Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005).

    CAS  PubMed  Google Scholar 

  2. Dunn, E., Sims, J.E., Nicklin, M.J. & O'Neill, L.A. Annotating genes with potential roles in the immune system: six new members of the IL-1 family. Trends Immunol. 22, 533–536 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Priestle, J.P., Schar, H.P. & Grutter, M.G. Crystallographic refinement of interleukin 1 beta at 2.0 A resolution. Proc. Natl. Acad. Sci. USA 86, 9667–9671 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pan, G. et al. IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 13, 1–7 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Bufler, P. et al. A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity. Proc. Natl. Acad. Sci. USA 99, 13723–13728 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kumar, S. et al. Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine 18, 61–71 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Busfield, S.J. et al. Identification and gene organization of three novel members of the IL-1 family on human chromosome 2. Genomics 66, 213–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Kumar, S. et al. Identification and initial characterization of four novel members of the interleukin-1 family. J. Biol. Chem. 275, 10308–10314 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Smith, D.E. et al. Four new members expand the interleukin-1 superfamily. J. Biol. Chem. 275, 1169–1175 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Taylor, S.L., Renshaw, B.R., Garka, K.E., Smith, D.E. & Sims, J.E. Genomic organization of the interleukin-1 locus. Genomics 79, 726–733 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Novick, D. et al. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 10, 127–136 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Nold, M. et al. IL-18BPa:Fc cooperates with immunosuppressive drugs in human whole blood. Biochem. Pharmacol. 66, 505–510 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Sharma, S. et al. The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines. J. Immunol. 180, 5477–5482 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Bufler, P., Gamboni-Robertson, F., Azam, T., Kim, S.H. & Dinarello, C.A. Interleukin-1 homologues IL-1F7b and IL-18 contain functional mRNA instability elements within the coding region responsive to lipopolysaccharide. Biochem. J. 381, 503–510 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lai, J.P. et al. Full-length and truncated neurokinin-1 receptor expression and function during monocyte/macrophage differentiation. Proc. Natl. Acad. Sci. USA 103, 7771–7776 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grimsby, S. et al. Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits its transcriptional activity. FEBS Lett. 577, 93–100 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Kjellman, C. et al. Identification and characterization of a human smad3 splicing variant lacking part of the linker region. Gene 327, 141–152 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Jinnin, M., Ihn, H. & Tamaki, K. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol. Pharmacol. 69, 597–607 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Dillon, S. et al. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J. Immunol. 172, 4733–4743 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Andre, S., Tough, D.F., Lacroix-Desmazes, S., Kaveri, S.V. & Bayry, J. Surveillance of antigen-presenting cells by CD4+ CD25+ regulatory T cells in autoimmunity: immunopathogenesis and therapeutic implications. Am. J. Pathol. 174, 1575–1587 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Werner, F. et al. Transforming growth factor-beta 1 inhibition of macrophage activation is mediated via Smad3. J. Biol. Chem. 275, 36653–36658 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Li, M.O. & Flavell, R.A. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity 28, 468–476 (2008).

    Article  PubMed  Google Scholar 

  23. Trotta, R. et al. TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J. Immunol. 181, 3784–3792 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Musso, T. et al. Transforming growth factor beta downregulates interleukin-1 (IL-1)-induced IL-6 production by human monocytes. Blood 76, 2466–2469 (1990).

    CAS  PubMed  Google Scholar 

  25. Larmonier, N. et al. Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol. Immunother. 56, 48–59 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Misra, N., Bayry, J., Lacroix-Desmazes, S., Kazatchkine, M.D. & Kaveri, S.V. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J. Immunol. 172, 4676–4680 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Bayry, J., Triebel, F., Kaveri, S.V. & Tough, D.F. Human dendritic cells acquire a semimature phenotype and lymph node homing potential through interaction with CD4+CD25+ regulatory T cells. J. Immunol. 178, 4184–4193 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Fogel-Petrovic, M. et al. Physiological concentrations of transforming growth factor beta1 selectively inhibit human dendritic cell function. Int. Immunopharmacol. 7, 1924–1933 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Laouar, Y. et al. TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 105, 10865–10870 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cohen, I. et al. Differential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc. Natl. Acad. Sci. USA 107, 2574–2579.

    Article  CAS  Google Scholar 

  31. Werman, A. et al. The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription. Proc. Natl. Acad. Sci. USA 101, 2434–2439 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl. Acad. Sci. USA 104, 282–287 (2007).

    CAS  PubMed  Google Scholar 

  33. Wilson, K.C., Cruikshank, W.W., Center, D.M. & Zhang, Y. Prointerleukin-16 contains a functional CcN motif that regulates nuclear localization. Biochemistry 41, 14306–14312 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Yang, H., Wang, H. & Tracey, K.J. HMG-1 rediscovered as a cytokine. Shock 15, 247–253 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Kleemann, R. et al. Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408, 211–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Dinarello, C.A. Blocking IL-1 in systemic inflammation. J. Exp. Med. 201, 1355–1359 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ross, J.A., Nagy, Z.S., Cheng, H., Stepkowski, S.M. & Kirken, R.A. Regulation of T cell homeostasis by JAKs and STATs. Arch. Immunol. Ther. Exp. (Warsz.) 55, 231–245 (2007).

    Article  CAS  Google Scholar 

  38. Ulloa, L., Doody, J. & Massague, J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397, 710–713 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Zauberman, A., Lapter, S. & Zipori, D. Smad proteins suppress CCAAT/enhancer-binding protein (C/EBP) beta- and STAT3-mediated transcriptional activation of the haptoglobin promoter. J. Biol. Chem. 276, 24719–24725 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Foster, L.C. et al. Role of activating protein-1 and high mobility group-I(Y) protein in the induction of CD44 gene expression by interleukin-1beta in vascular smooth muscle cells. FASEB J. 14, 368–378 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Imai, K., Takeshita, A. & Hanazawa, S. Transforming growth factor-beta inhibits lipopolysaccharide-stimulated expression of inflammatory cytokines in mouse macrophages through downregulation of activation protein 1 and CD14 receptor expression. Infect. Immun. 68, 2418–2423 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schieven, G.L. The biology of p38 kinase: a central role in inflammation. Curr. Top. Med. Chem. 5, 921–928 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Martin, M., Rehani, K., Jope, R.S. & Michalek, S.M. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6, 777–784 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McCartney-Francis, N., Jin, W. & Wahl, S.M. Aberrant Toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-beta 1 signaling pathway. J. Immunol. 172, 3814–3821 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Nold, M.F. et al. Endogenous IL-32 controls cytokine and HIV-1 production. J. Immunol. 181, 557–565 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank F. Gamboni-Robertson and F. Eckerdt (both University of Colorado, Denver) for advice on immunofluorescence; T. Azam, T. Goncharov (both University of Colorado, Denver) and M. Fink (Ludwig-Maximilians University Munich) for assistance; L. Joosten (Radboud University Nijmegen) for performing immunohistochemistry; D. Finkel (R&D Systems) for assistance regarding the protein arrays; and P. Pagel (University of Technology Munich) for database research for IL-37-interacting molecules. Supported by the US National Institutes of Health (AI-15614 and CA-04 6934 to C.A.D.) and the Deutsche Forschungsgemeinschaft (747/1-1 to M.F.N. and Bu 1222/3-1, 3-2 and 3-3 to P.B.).

Author information

Authors and Affiliations

Authors

Contributions

M.F.N., C.A.N.-P., P.B. and C.A.D. designed the study, analyzed the data and wrote the manuscript. M.F.N., C.A.N.-P., J.A.Z. and P.B. did experiments. B.E.P. was in charge of the flow-cytometry analysis.

Corresponding author

Correspondence to Charles A Dinarello.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–3 (PDF 1108 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nold, M., Nold-Petry, C., Zepp, J. et al. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 11, 1014–1022 (2010). https://doi.org/10.1038/ni.1944

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1944

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing