Skip to main content

Advertisement

SpringerLink
Log in

IL-1 Receptor Accessory Protein-Ig/IL-1 Receptor Type II-Ig Heterodimer Inhibits IL-1 Response More Strongly than Other IL-1 Blocking Biopharmaceutical Agents

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Introduction

Interleukin (IL)-1 is a key orchestrator of inflammation and IL-1 inhibitors are expected to be promising pharmaceutical agents for such pathologies. IL-1 is bound to the complex of two receptor components with much higher affinity than with either receptor component alone.

Materials and Methods

We examined the effect of a heterodimer of IL-1 receptor accessory protein (Acp)-immunoglobulin (Ig) and IL-1R type II (IL1R2)-Ig named AcP-Ig/IL1R2-Ig heterodimer, and compared its effects with other IL-1 inhibitors reported previously.

Results and Discussion

Our results demonstrated that the rat AcP-Ig/IL1R2-Ig heterodimer (IC50 = 1.95 pM) inhibited IL-1 response to a greater extent than IL1RA (IC50 = 1,935 pM), Acp-IL1R type I (IL1R1)-Ig homodimer (IC50 = 73.7 pM) and Acp-IL1R2-Ig homodimer (IC50 = 72.8 pM). Moreover, human AcP-Ig/IL1R2-Ig heterodimer (IC50 = 0.14 pM) inhibited it to a greater extent than Acp-IL1R1-Ig homodimer (IC50 = 4.48 pM) and strongly inhibited responses of both IL-1α and IL-1β.

Conclusions

The AcP-Ig/IL1R2-Ig heterodimer, which is similar to the original extracellular structure of the Acp/IL1R1 complex, may inhibit the IL-1 response more vigorously than other IL-1 blocking biopharmaceutical agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

Acp:

IL-1 receptor accessory protein

AcP-Ig/IL1R2-Ig heterodimer:

Acp-Ig and IL1R2-Ig heterodimer

CM:

Conditioned medium

EAM:

Experimental autoimmune myocarditis

Glu:

Glucagon

GRO2αC:

C-terminal sites of GRO2α

GRO2αN:

N-terminal sites of GRO2α

Ig:

Immunoglobulin

IL:

Interleukin

IL1R1:

IL-1R type I

IL1R2:

IL-1R type II

IL1RA:

IL-1 receptor antagonist

PCR:

Polymerase chain reaction

References

  1. Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood. 1991;77:1627–52.

    PubMed  CAS  Google Scholar 

  2. Arend WP, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995;38:151–60.

    Article  PubMed  CAS  Google Scholar 

  3. Dinarello CA, Donath MY, Mandrup-Poulsen T. Role of IL-1beta in type 2 diabetes. Curr Opin Endocrinol Diab Obes. 2010;17:314–21.

    CAS  Google Scholar 

  4. Moyer CF, Sajuthi D, Tulli H, Williams JK. Synthesis of IL-1 alpha and IL-1 beta by arterial cells in atherosclerosis. Am J Pathol. 1991;138:951–60.

    PubMed  CAS  Google Scholar 

  5. Garces K. Anakinra: interleukin-1 receptor antagonist therapy for rheumatoid arthritis. Issues Emerg Health Technol. 2001;16:1–4.

    PubMed  Google Scholar 

  6. Liao Z, Grimshaw RS, Rosenstreich DL. Identification of a specific interleukin 1 inhibitor in the urine of febrile patients. J Exp Med. 1984;159:126–36.

    Article  PubMed  CAS  Google Scholar 

  7. Larsen CM, Faulenbach M, Vaag A, Ehses JA, Donath MY, Mandrup-Poulsen T. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diab Care. 2009;32:1663–8.

    Article  CAS  Google Scholar 

  8. Viguier M, Guigue P, Pages C, Smahi A, Bachelez H. Successful treatment of generalized pustular psoriasis with the interleukin-1-receptor antagonist Anakinra: lack of correlation with IL1RN mutations. Ann Intern Med. 2010;153:66–7.

    PubMed  Google Scholar 

  9. El-Osta H, Janku F, Kurzrock R. Successful treatment of Castleman’s disease with interleukin-1 receptor antagonist (Anakinra). Mol Cancer Ther. 2010;9:1485–8.

    Article  PubMed  CAS  Google Scholar 

  10. Arend WP, Welgus HG, Thompson RC, Eisenberg SP. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. 1990;85:1694–7.

    Article  PubMed  CAS  Google Scholar 

  11. Economides AN, Carpenter LR, Rudge JS, Wong V, Koehler-Stec EM, Hartnett C, et al. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med. 2003;9:47–52.

    Article  PubMed  CAS  Google Scholar 

  12. Wang D, Zhang S, Li L, Liu X, Mei K, Wang X. Structural insights into the assembly and activation of IL-1beta with its receptors. Nat Immunol. 2010;11(10):905–11.

    Article  PubMed  CAS  Google Scholar 

  13. Symons JA, Young PR, Duff GW. Soluble type II interleukin 1 (IL-1) receptor binds and blocks processing of IL-1 beta precursor and loses affinity for IL-1 receptor antagonist. Proc Natl Acad Sci USA. 1995;92:1714–8.

    Article  PubMed  CAS  Google Scholar 

  14. Kodama M, Matsumoto Y, Fujiwara M, Masani F, Izumi T, Shibata A. A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction. Clin Immunol Immunopathol. 1990;57:250–62.

    Article  PubMed  CAS  Google Scholar 

  15. Nishino T, Kodaira T, Shin S, Imagawa K, Shima K, Kumahara Y, et al. Glucagon radioimmunoassay with use of antiserum to glucagon C-terminal fragment. Clin Chem. 1981;27:1690–7.

    PubMed  CAS  Google Scholar 

  16. Hanawa H, Watanabe R, Hayashi M, Yoshida T, Abe S, Komura S, et al. A novel method to assay proteins in blood plasma after intravenous injection of plasmid DNA. Tohoku J Exp Med. 2004;202:155–61.

    Article  PubMed  CAS  Google Scholar 

  17. Yoshida T, Hanawa H, Toba K, Watanabe H, Watanabe R, Yoshida K, et al. Expression of immunological molecules by cardiomyocytes and inflammatory and interstitial cells in rat autoimmune myocarditis. Cardiovasc Res. 2005;68:278–88.

    Article  PubMed  CAS  Google Scholar 

  18. Mertens M, Singh JA. Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol. 2009;36:1118–25.

    Article  PubMed  CAS  Google Scholar 

  19. Koike R, Takeuchi T, Eguchi K, Miyasaka N. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod Rheumatol. 2007;17:451–8.

    Article  PubMed  CAS  Google Scholar 

  20. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.

    Article  PubMed  CAS  Google Scholar 

  21. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.

    Article  PubMed  CAS  Google Scholar 

  22. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–65.

    Article  PubMed  CAS  Google Scholar 

  23. Smith DE, Hanna R, Della F, Moore H, Chen H, Farese AM, et al. The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action. Immunity. 2003;18:87–96.

    Article  PubMed  CAS  Google Scholar 

  24. Greenwald J, Groppe J, Gray P, Wiater E, Kwiatkowski W, Vale W, et al. The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol Cell. 2003;11:605–17.

    Article  PubMed  CAS  Google Scholar 

  25. LaPorte SL, Juo ZS, Vaclavikova J, Colf LA, Qi X, Heller NM, et al. Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell. 2008;132:259–72.

    Article  PubMed  CAS  Google Scholar 

  26. Boulanger MJ, Chow DC, Brevnova EE, Garcia KC. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003;300:2101–4.

    Article  PubMed  CAS  Google Scholar 

  27. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. J. Miyazaki (Division of Stem Cell Regulation Research, G6, Osaka University Medical School) for providing us with the pCAGGS plasmid vector. This study was supported in part by a Ministry of Health, Labor, and Welfare in Japan Grant “Research on Regulatory Science of Pharmaceutical and Medical Devices.” and by a Grant for scientific research from the Ministry of Education, Science and Culture of Japan (number 20591185).

Conflicts of Interest

No conflict of interest has been declared by the authors.

Author information

Authors and Affiliations

  1. Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8120, Japan

    Haruo Hanawa, Limin Ding, He Chang, Kaori Yoshida, Keita Otaki, Kazuhisa Hao, Sou Kasahara, Makoto Kodama & Yoshifusa Aizawa

  2. Department of Medical Technology, School of Health Sciences, Faculty of Medicine, Niigata University, Niigata, Japan

    Yoshimi Ota & Mikio Nakazawa

Authors
  1. Haruo Hanawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshimi Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Limin Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. He Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kaori Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keita Otaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuhisa Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sou Kasahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Makoto Kodama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mikio Nakazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yoshifusa Aizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haruo Hanawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hanawa, H., Ota, Y., Ding, L. et al. IL-1 Receptor Accessory Protein-Ig/IL-1 Receptor Type II-Ig Heterodimer Inhibits IL-1 Response More Strongly than Other IL-1 Blocking Biopharmaceutical Agents. J Clin Immunol 31, 455–464 (2011). https://doi.org/10.1007/s10875-010-9497-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-010-9497-z

Keywords

Search

Navigation