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.

Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors

Abstract

Tumor necrosis factor (TNF)-α has an important role in the pathogenesis of autoimmune and inflammatory diseases such as rheumatoid and septic arthritis. The biological effects of TNF-α are mediated by binding to TNF receptors TNFR1 (also known as P60) or TNFR2 (also known as P80). The pre-ligand assembly domain (PLAD) is a portion of the extracellular region of TNFRs that mediates receptor-chain association essential for signaling. We found that soluble versions of PLAD, especially those derived from P60, block the biochemical effects of TNF-α in vitro and potently inhibit arthritis in animal models. Thus, targeting the PLAD may have clinical value in the treatment of human arthritis and other disorders involving receptors of the TNFR superfamily.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Expression of recombinant bacterial PLAD proteins.
Figure 2: Effects of PLAD proteins in TNF-α–induced cell death.
Figure 3: Effects of P60 and P80 PLAD proteins on arthritis induced by intra-articular injection of TNF-α in BALB/c mice and bacterial CpG DNA in C3H/HeJ mice.
Figure 4: Effects of P60 and P80 PLAD proteins on CIA in DBA/1J mice.
Figure 5: TNFR expression in arthritic joints and PLAD protein inhibition of TNF-α binding and NF-κB activation.
Figure 6: P60 PLAD protein inhibits osteoclastogenesis and RANK and RANKL expression.

Accession codes

Accessions

BINDPlus

References

  1. Tracey, K.J. & Cerami, A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu. Rev. Med. 45, 491–503 (1994).

    Article  CAS  Google Scholar 

  2. Feldmann, M. & Maini, R.N. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat. Med. 9, 1245–1250 (2003).

    Article  CAS  Google Scholar 

  3. Hultgren, O., Eugster, H.P., Sedgwick, J.D., Korner, H. & Tarkowski, A. TNF/lymphotoxin-alpha double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus. J. Immunol. 161, 5937–5942 (1998).

    CAS  PubMed  Google Scholar 

  4. Deng, G.M., Nilsson, I.M., Verdrengh, M., Collins, L.V. & Tarkowski, A. Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat. Med. 5, 702–705 (1999).

    Article  CAS  Google Scholar 

  5. Gutierrez-Ramos, J.C. & Bluethmann, H. Molecules and mechanisms operating in septic shock: lessons from knockout mice. Immunol. Today 18, 329–334 (1997).

    Article  CAS  Google Scholar 

  6. Locksley, R.M., Killeen, N. & Lenardo, M.J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001).

    Article  CAS  Google Scholar 

  7. Chan, F.K. et al. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288, 2351–2354 (2000).

    Article  CAS  Google Scholar 

  8. Siegel, R.M. et al. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288, 2354–2357 (2000).

    Article  CAS  Google Scholar 

  9. Siegel, R.M., Chan, F.K., Chun, H.J. & Lenardo, M.J. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat. Immunol. 1, 469–474 (2000).

    Article  CAS  Google Scholar 

  10. Chan, F.K. The pre-ligand binding assembly domain: a potential target of inhibition of tumour necrosis factor receptor function. Ann. Rheum. Dis. 59 Suppl 1, i50–i53 (2000).

    Article  CAS  Google Scholar 

  11. Feldmann, M., Brennan, F.M. & Maini, R.N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).

    Article  CAS  Google Scholar 

  12. Miossec, P. Cytokine abnormalities in inflammatory arthritis. Baillieres Clin. Rheumatol. 6, 373–392 (1992).

    Article  CAS  Google Scholar 

  13. Pettipher, E.R., Higgs, G.A. & Henderson, B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc. Natl. Acad. Sci. USA 83, 8749–8753 (1986).

    Article  CAS  Google Scholar 

  14. Henderson, B. & Pettipher, E.R. Arthritogenic actions of recombinant IL-1 and tumour necrosis factor alpha in the rabbit: evidence for synergistic interactions between cytokines in vivo. Clin. Exp. Immunol. 75, 306–310 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakashima, T., Wada, T. & Penninger, J.M. RANKL and RANK as novel therapeutic targets for arthritis. Curr. Opin. Rheumatol. 15, 280–287 (2003).

    Article  CAS  Google Scholar 

  16. Deng, G.M., Verdrengh, M., Liu, Z.Q. & Tarkowski, A. The major role of macrophages and their product tumor necrosis factor alpha in the induction of arthritis triggered by bacterial DNA containing CpG motifs. Arthritis Rheum. 43, 2283–2289 (2000).

    Article  CAS  Google Scholar 

  17. Williams, R.O., Feldmann, M. & Maini, R.N. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. USA 89, 9784–9788 (1992).

    Article  CAS  Google Scholar 

  18. Sheehan, K.C., Pinckard, J.K., Arthur, C.D., Dehner, L.P., Goeddel, D.V. & Schreiber, R.D. Monoclonal antibodies specific for murine p55 and p75 tumor necrosis factor receptors: identification of a novel in vivo role for p75. J. Exp. Med. 181, 607–617 (1995).

    Article  CAS  Google Scholar 

  19. Chan, F.K. & Lenardo, M.J. A crucial role for p80 TNF-R2 in amplifying p60 TNF-R1 apoptosis signals in T lymphocytes. Eur. J. Immunol. 30, 652–660 (2000).

    Article  CAS  Google Scholar 

  20. Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).

    Article  CAS  Google Scholar 

  21. Chen, G. & Goeddel, D.V. TNF-R1 signaling: a beautiful pathway. Science 31, 1634–1635 (2002).

    Article  Google Scholar 

  22. Su, H. et al. Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science 307, 1465–1468 (2005).

    Article  CAS  Google Scholar 

  23. Redlich, K. et al. Osteoclasts are essential for TNF-alpha-mediated joint destruction. J. Clin. Invest. 110, 1419–1427 (2002).

    Article  CAS  Google Scholar 

  24. Pondel, M. Calcitonin and calcitonin receptors: bone and beyond. Int. J. Exp. Pathol. 81, 405–422 (2000).

    Article  CAS  Google Scholar 

  25. Boyle, W.J., Simonet, W.S. & Lacey, D.L. Osteoclast differentiation and activation. Nature 423, 337–342 (2003).

    Article  CAS  Google Scholar 

  26. Mori, L., Iselin, S., De Libero, G. & Lesslauer, W. Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice. J. Immunol. 157, 3178–3182 (1996).

    CAS  PubMed  Google Scholar 

  27. Jimi, E. et al. Selective inhibition of NF-kappa B blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat. Med. 10, 617–624 (2004).

    Article  CAS  Google Scholar 

  28. Gomez-Reino, J.J., Carmona, L., Valverde, V.R., Mola, E.M., Montero, M.D. & BIOBADASER Group. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 48, 2122–2127 (2003).

    Article  CAS  Google Scholar 

  29. Wolfe, F., Michaud, K., Anderson, J. & Urbansky, K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum. 50, 372–379 (2004).

    Article  CAS  Google Scholar 

  30. Shakoor, N., Michalska, M., Harris, C.A. & Block, J.A. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 359, 579–580 (2002).

    Article  CAS  Google Scholar 

  31. Wolfe, F. & Michaud, K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum. 50, 1740–1751 (2004).

    Article  CAS  Google Scholar 

  32. Elliott, M.J. et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 344, 1125–1127 (1994).

    Article  CAS  Google Scholar 

  33. Jarvis, B. & Faulds, D. Etanercept: a review of its use in rheumatoid arthritis. Drugs 57, 945–966 (1999).

    Article  CAS  Google Scholar 

  34. Zhang, Z., Jimi, E. & Bothwell, A.L. Receptor activator of NF-kappa B ligand stimulates recruitment of SHP-1 to the complex containing TNFR-associated factor 6 that regulates osteoclastogenesis. J. Immunol. 171, 3620–3626 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Su, C. Trageser, N. Bidere and L. Yu for experimental assistance and R. Siegel, D. Bolton and K. Sakai for critically reading the manuscript. G.-M.D. is supported by a Pharmacology Research Associate Training fellowship of the National Institute of General Medical Science. We thank O. Schwartz and the microscopy group of the National Institute of Allergy and Infectious Disease, National Institutes of Health for confocal microscopy help and J. Qin for statistical help. This work was supported by the intramural program of the National Institute of Allergy and Infectious Disease, US National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Lenardo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Amino acid sequences of human PLAD-GST fusion proteins in standard single-letter code. (PDF 141 kb)

Supplementary Fig. 2

Effects of P60 PLAD protein on TNF-α–induced cell death in L929 cells. (PDF 286 kb)

Supplementary Fig. 3

Effects of GST protein and P80 PLAD protein on inflammatory arthritis. (PDF 1414 kb)

Supplementary Fig. 4

Photomicrographs of immunohistochemistry. (PDF 5160 kb)

Supplementary Fig. 5

Immunogenicity and half-life of the P60 PLAD protein. (PDF 196 kb)

Supplementary Fig. 6

PLAD proteins inhibit TNF-α–induced IκBα degradation. (PDF 462 kb)

Supplementary Fig. 7

Gel electrophoresis of 50 ng of human TNF-α immunoprecipitated (IP) with different amounts of etanercept and P60 PLAD protein. (PDF 207 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Deng, GM., Zheng, L., Ka-Ming Chan, F. et al. Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Nat Med 11, 1066–1072 (2005). https://doi.org/10.1038/nm1304

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1304

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