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.

Interleukin receptor activates a MYD88–ARNO–ARF6 cascade to disrupt vascular stability

Nature volume 492, pages 252–255 (2012)Cite this article

Subjects

Abstract

The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1β (IL-1β), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-κB (NF-κB)-dependent transcriptional pathway that results in inflammatory-cell activation and recruitment1,2,3,4. Endothelial cells, which usually serve as a barrier to the movement of inflammatory cells out of the blood and into tissue, are also critical mediators of the inflammatory response5,6. Paradoxically, the cytokines vital to a successful immune defence also have disruptive effects on endothelial cell–cell interactions and can trigger degradation of barrier function and dissociation of tissue architecture7,8,9. The mechanism of this barrier dissolution and its relationship to the canonical NF-κB pathway remain poorly defined. Here we show that the direct, immediate and disruptive effects of IL-1β on endothelial stability in a human in vitro cell model are NF-κB independent and are instead the result of signalling through the small GTPase ADP-ribosylation factor 6 (ARF6) and its activator ARF nucleotide binding site opener (ARNO; also known as CYTH2). Moreover, we show that ARNO binds directly to the adaptor protein MYD88, and thus propose MYD88–ARNO–ARF6 as a proximal IL-1β signalling pathway distinct from that mediated by NF-κB. Finally, we show that SecinH3, an inhibitor of ARF guanine nucleotide-exchange factors such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Immediate effects of IL-1β are NF-κB independent and ARF6 dependent.
Figure 2: Inhibition of ARF-GAPs and ARF-GEFs affect ARF6 activation and VE-cadherin localization.
Figure 3: The immediate IL-1β-induced permeability pathway diverges at MYD88.
Figure 4: Inhibition of ARF-GEFs decreases collagen-induced vascular permeability and arthritis in mice.

References

  1. Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725–734 (2002)

    Article  CAS  Google Scholar 

  2. Collins, T. et al. Transcriptional regulation of endothelial cell adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J. 9, 899–909 (1995)

    Article  CAS  Google Scholar 

  3. Liu, S. F. & Malik, A. B. NF-κB activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L622–L645 (2006)

    Article  CAS  Google Scholar 

  4. Rothwarf, D. M. & Karin, M. The NF-κB activation pathway: a paradigm in information transfer from membrane to nucleus. Sci. STKE 1999, RE1 (1999)

    CAS  PubMed  Google Scholar 

  5. Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nature Rev. Immunol. 7, 803–815 (2007)

    Article  CAS  Google Scholar 

  6. Muller, W. A. Leukocyte–endothelial cell interactions in the inflammatory response. Lab. Invest. 82, 521–533 (2002)

    Article  CAS  Google Scholar 

  7. Royall, J. A. et al. Tumor necrosis factor and interleukin 1 alpha increase vascular endothelial permeability. Am. J. Physiol. Lung Cell. Mol. Physiol. 257, L399–L410 (1989)

    Article  CAS  Google Scholar 

  8. West, X. Z. et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467, 972–976 (2010)

    Article  ADS  CAS  Google Scholar 

  9. London, N. R. et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci. Transl. Med. 2, 23ra19 (2010)

    Article  Google Scholar 

  10. Zhu, J. & Mohan, C. Toll-like receptor signaling pathways–therapeutic opportunities. Mediators Inflamm. 2010, 781235 (2010)

    Article  Google Scholar 

  11. Kishore, N. et al. A selective IKK-2 inhibitor blocks NF-κB-dependent gene expression in interleukin-1β-stimulated synovial fibroblasts. J. Biol. Chem. 278, 32861–32871 (2003)

    Article  CAS  Google Scholar 

  12. Matthews, J. S. & O’Neill, L. A. Distinct roles for p42/p44 and p38 mitogen-activated protein kinases in the induction of IL-2 by IL-1. Cytokine 11, 643–655 (1999)

    Article  CAS  Google Scholar 

  13. Martin, M. U. & Wesche, H. Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family. Biochim. Biophys. Acta 1592, 265–280 (2002)

    Article  CAS  Google Scholar 

  14. Kaltschmidt, B., Linker, R. A., Deng, J. & Kaltschmidt, C. Cyclooxygenase-2 is a neuronal target gene of NF-κB. BMC Mol. Biol. 3, 16 (2002)

    Article  Google Scholar 

  15. Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875 (2001)

    Article  ADS  CAS  Google Scholar 

  16. Palacios, F., Price, L., Schweitzer, J., Collard, J. G. & D’Souza-Schorey, C. An essential role for ARF6-regulated membrane traffic in adherens junction turnover and epithelial cell migration. EMBO J. 20, 4973–4986 (2001)

    Article  CAS  Google Scholar 

  17. D’Souza-Schorey, C., Li, G., Colombo, M. I. & Stahl, P. D. A regulatory role for ARF6 in receptor-mediated endocytosis. Science 267, 1175–1178 (1995)

    Article  ADS  Google Scholar 

  18. Riley, K. N., Maldonado, A. E., Tellier, P., D’Souza-Schorey, C. & Herman, I. M. Betacap73–ARF6 interactions modulate cell shape and motility after injury in vitro. Mol. Biol. Cell 14, 4155–4161 (2003)

    Article  CAS  Google Scholar 

  19. Zhang, Q. et al. Small-molecule synergist of the Wnt/β-catenin signaling pathway. Proc. Natl Acad. Sci. USA 104, 7444–7448 (2007)

    Article  ADS  CAS  Google Scholar 

  20. Hafner, M. et al. Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature 444, 941–944 (2006)

    Article  ADS  CAS  Google Scholar 

  21. Béraud-Dufour, S. et al. A glutamic finger in the guanine nucleotide exchange factor ARNO displaces Mg2+ and the β-phosphate to destabilize GDP on ARF1. EMBO J. 17, 3651–3659 (1998)

    Article  Google Scholar 

  22. Arend, W. P. Cytokine imbalance in the pathogenesis of rheumatoid arthritis: the role of interleukin-1 receptor antagonist. Semin. Arthritis Rheum. 30, 1–6 (2001)

    Article  CAS  Google Scholar 

  23. Szekanecz, Z. & Koch, A. E. Vascular involvement in rheumatic diseases: ‘vascular rheumatology’. Arthritis Res. Ther. 10, 224 (2008)

    Article  Google Scholar 

  24. van den Berg, W. B., Joosten, L. A., Helsen, M. & van de Loo, F. A. Amelioration of established murine collagen-induced arthritis with anti-IL-1 treatment. Clin. Exp. Immunol. 95, 237–243 (1994)

    Article  CAS  Google Scholar 

  25. Joosten, L. A., Helsen, M. M., van de Loo, F. A. & van den Berg, W. B. Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. A comparative study using anti-TNFα, anti-IL-1α/β, and IL-1Ra. Arthritis Rheum. 39, 797–809 (1996)

    Article  CAS  Google Scholar 

  26. Wooley, P. H., Dutcher, J., Widmer, M. B. & Gillis, S. Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice. J. Immunol. 151, 6602–6607 (1993)

    CAS  PubMed  Google Scholar 

  27. London, N. R., Whitehead, K. J. & Li, D. Y. Endogenous endothelial cell signaling systems maintain vascular stability. Angiogenesis 12, 149–158 (2009)

    Article  CAS  Google Scholar 

  28. Keane, J. et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001)

    Article  CAS  Google Scholar 

  29. Lee, W. L. & Slutsky, A. S. Sepsis and endothelial permeability. N. Engl. J. Med. 363, 689–691 (2010)

    Article  CAS  Google Scholar 

  30. Silva, L. C., Ortigosa, L. C. & Benard, G. Anti-TNF-α agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls. Immunotherapy 2, 817–833 (2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Lim and T. Mleynek for graphical assistance, G. Zimmerman and J. Kaplan for reading the manuscript, S. Odelberg for reading the manuscript and statistical analysis, J. Ling for help with immunostaining, R. Campbell and A. Weyrich for providing primary human blood cells, C. Rodesch and the University of Utah Cell Imaging/Fluorescence Facility as well as the University of Utah Flow Cytometry Facility, and M. P. Revelo for help with pathology. D.Y.L. and his laboratory were funded by grants from the National Heart, Lung, and Blood Institute; Burroughs Wellcome Fund; Juvenile Diabetes Research Foundation; NIAID Rocky Mountain Regional Center of Excellence in Biodefense and Emerging Infectious Disease; the American Asthma Foundation; and the Department of Defense. D.Y.L. is the HA and Edna Benning Endowed Professor of Medicine and Cardiology.

Author information

Author notes

  1. Weiquan Zhu, Nyall R. London and Christopher C. Gibson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of Utah, Salt Lake City, 84112, Utah, USA

    Weiquan Zhu, Nyall R. London, Jinping Guo, Matthew C. P. Smith, Kirk R. Thomas & Dean Y. Li

  2. Program in Molecular Medicine, University of Utah, Salt Lake City, 84112, Utah, USA

    Weiquan Zhu, Nyall R. London, Christopher C. Gibson, Chadwick T. Davis, Lise K. Sorensen, Dallas S. Shi, Jinping Guo, Matthew C. P. Smith, Allie H. Grossmann, Kirk R. Thomas & Dean Y. Li

  3. Department of Oncological Sciences, University of Utah, Salt Lake City, 84112, Utah, USA

    Nyall R. London, Matthew C. P. Smith & Dean Y. Li

  4. Department of Bioengineering, University of Utah, Salt Lake City, 84112, Utah, USA

    Christopher C. Gibson

  5. Department of Human Genetics, University of Utah, Salt Lake City, 84112, Utah, USA

    Chadwick T. Davis & Dallas S. Shi

  6. Navigen Inc, Salt Lake City, 84112, Utah, USA

    Zongzhong Tong

  7. Department of Anatomy, Second Military Medical University, Shanghai, 200433, China

    Jinping Guo

  8. Department of Pathology, University of Utah, Salt Lake City, 84112, Utah, USA

    Allie H. Grossmann

  9. Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, 84112, Utah, USA

    Dean Y. Li

  10. The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China,

    Dean Y. Li

Authors
  1. Weiquan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nyall R. London
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher C. Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chadwick T. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zongzhong Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lise K. Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dallas S. Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jinping Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Matthew C. P. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Allie H. Grossmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kirk R. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dean Y. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.Z., N.R.L., C.C.G. and D.Y.L. were responsible for project conceptualization, experimental design, data analysis and manuscript preparation. W.Z., C.C.G., C.T.D., Z.T., L.K.S., D.S.S. and J.G. performed and collected data for in vitro experiments. N.R.L. collected data for in vivo experiments. C.C.G. developed software techniques for immunofluorescence analysis. M.C.P.S. performed flow cytometry experiments. Z.T. and K.R.T. made constructs and adenoviruses. A.H.G. provided histology and pathology expertise. D.Y.L. was responsible for funding the project.

Corresponding author

Correspondence to Dean Y. Li.

Ethics declarations

Competing interests

The University of Utah has filed intellectual property concerning targeting signalling pathways to treat inflammatory arthritis. The University of Utah has licensed technology to Navigen, a biotechnology company owned in part by the University of Utah Research Foundation. N.R.L. and W.Z. are paid consultants for Navigen and D.Y.L. is a co-founder of Navigen.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-9, Supplementary Methods and Supplementary References. This file was replaced on December 19th 2012. (PDF 2295 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhu, W., London, N., Gibson, C. et al. Interleukin receptor activates a MYD88–ARNO–ARF6 cascade to disrupt vascular stability. Nature 492, 252–255 (2012). https://doi.org/10.1038/nature11603

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11603

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced 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