Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 May;93(5):2114–2119. doi: 10.1172/JCI117206

Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis.

F De Benedetti 1, M Massa 1, P Pignatti 1, S Albani 1, D Novick 1, A Martini 1
PMCID: PMC294340  PMID: 8182142

Abstract

By using a sandwich ELISA, soluble human IL-6 receptor (sIL-6 R) levels were measured in the sera of 20 healthy children and of 25 patients with systemic juvenile rheumatoid arthritis (JRA). In patients with systemic JRA, serum sIL-6 R levels (114.6 +/- 37.7 ng/ml) were significantly lower (P < 0.01) than those of healthy children (161.2 +/- 45.5 ng/ml). Serum sIL-6 R levels were negatively correlated (r = -0.610, P < 0.001) with serum IL-6 levels measured with the B9 cells. The serum IL-6/sIL-6 R complex was detected using an ELISA based on a monoclonal antibody to IL-6 for capture and on a monoclonal antibody to human sIL-6 R for detection. Healthy controls had little, if any, detectable serum IL-6/sIL-6 R complex (OD 0.024 +/- 0.027), while the majority of patients with systemic JRA presented measurable serum IL-6/sIL-6 R complex (OD 0.492 +/- 0.546). IL-6 levels estimated in the circulating IL-6/sIL-6 R complexes were in the range of nanograms per milliliter and approximately 20-fold higher than those measured by the B9 cells. Since serum C-reactive protein concentrations were much more correlated with serum levels of IL-6/sIL-6 R complexes (r = 0.713, r2 = 0.51, P < 0.0001) than with the serum IL-6 levels measured with the B9 cells (r = 0.435, r2 = 0.19, P = 0.05), the large quantities of serum IL-6 present in IL-6/sIL-6 R complexes appear to be biologically relevant in vivo, at least as far as the induction by IL-6 of acute phase protein production.

Full text

PDF
2114

Images in this article

2116Image
on p.2116

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aderka D., Engelmann H., Maor Y., Brakebusch C., Wallach D. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med. 1992 Feb 1;175(2):323–329. doi: 10.1084/jem.175.2.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bataille R., Jourdan M., Zhang X. G., Klein B. Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. J Clin Invest. 1989 Dec;84(6):2008–2011. doi: 10.1172/JCI114392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brewer E. J., Jr, Bass J., Baum J., Cassidy J. T., Fink C., Jacobs J., Hanson V., Levinson J. E., Schaller J., Stillman J. S. Current proposed revision of JRA Criteria. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Section of The Arthritis Foundation. Arthritis Rheum. 1977 Mar;20(2 Suppl):195–199. [PubMed] [Google Scholar]
  4. De Benedetti F., Robbioni P., Massa M., Viola S., Albani S., Martini A. Serum interleukin-6 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis. Clin Exp Rheumatol. 1992 Sep-Oct;10(5):493–498. [PubMed] [Google Scholar]
  5. Fernandez-Botran R., Vitetta E. S. Evidence that natural murine soluble interleukin 4 receptors may act as transport proteins. J Exp Med. 1991 Sep 1;174(3):673–681. doi: 10.1084/jem.174.3.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fong Y., Moldawer L. L., Marano M., Wei H., Tatter S. B., Clarick R. H., Santhanam U., Sherris D., May L. T., Sehgal P. B. Endotoxemia elicits increased circulating beta 2-IFN/IL-6 in man. J Immunol. 1989 Apr 1;142(7):2321–2324. [PubMed] [Google Scholar]
  7. Gaillard J. P., Bataille R., Brailly H., Zuber C., Yasukawa K., Attal M., Maruo N., Taga T., Kishimoto T., Klein B. Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy. Eur J Immunol. 1993 Apr;23(4):820–824. doi: 10.1002/eji.1830230408. [DOI] [PubMed] [Google Scholar]
  8. Helfgott D. C., Tatter S. B., Santhanam U., Clarick R. H., Bhardwaj N., May L. T., Sehgal P. B. Multiple forms of IFN-beta 2/IL-6 in serum and body fluids during acute bacterial infection. J Immunol. 1989 Feb 1;142(3):948–953. [PubMed] [Google Scholar]
  9. Hirano T., Akira S., Taga T., Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today. 1990 Dec;11(12):443–449. doi: 10.1016/0167-5699(90)90173-7. [DOI] [PubMed] [Google Scholar]
  10. Hirano T., Matsuda T., Turner M., Miyasaka N., Buchan G., Tang B., Sato K., Shimizu M., Maini R., Feldmann M. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988 Nov;18(11):1797–1801. doi: 10.1002/eji.1830181122. [DOI] [PubMed] [Google Scholar]
  11. Honda M., Kitamura K., Mizutani Y., Oishi M., Arai M., Okura T., Igarahi K., Yasukawa K., Hirano T., Kishimoto T. Quantitative analysis of serum IL-6 and its correlation with increased levels of serum IL-2R in HIV-induced diseases. J Immunol. 1990 Dec 15;145(12):4059–4064. [PubMed] [Google Scholar]
  12. Honda M., Yamamoto S., Cheng M., Yasukawa K., Suzuki H., Saito T., Osugi Y., Tokunaga T., Kishimoto T. Human soluble IL-6 receptor: its detection and enhanced release by HIV infection. J Immunol. 1992 Apr 1;148(7):2175–2180. [PubMed] [Google Scholar]
  13. Houssiau F. A., Devogelaer J. P., Van Damme J., de Deuxchaisnes C. N., Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1988 Jun;31(6):784–788. doi: 10.1002/art.1780310614. [DOI] [PubMed] [Google Scholar]
  14. Jablons D. M., Mulé J. J., McIntosh J. K., Sehgal P. B., May L. T., Huang C. M., Rosenberg S. A., Lotze M. T. IL-6/IFN-beta-2 as a circulating hormone. Induction by cytokine administration in humans. J Immunol. 1989 Mar 1;142(5):1542–1547. [PubMed] [Google Scholar]
  15. Ludwig H., Nachbaur D. M., Fritz E., Krainer M., Huber H. Interleukin-6 is a prognostic factor in multiple myeloma. Blood. 1991 Jun 15;77(12):2794–2795. [PubMed] [Google Scholar]
  16. Lust J. A., Donovan K. A., Kline M. P., Greipp P. R., Kyle R. A., Maihle N. J. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine. 1992 Mar;4(2):96–100. doi: 10.1016/1043-4666(92)90043-q. [DOI] [PubMed] [Google Scholar]
  17. May L. T., Viguet H., Kenney J. S., Ida N., Allison A. C., Sehgal P. B. High levels of "complexed" interleukin-6 in human blood. J Biol Chem. 1992 Sep 25;267(27):19698–19704. [PubMed] [Google Scholar]
  18. Müllberg J., Schooltink H., Stoyan T., Günther M., Graeve L., Buse G., Mackiewicz A., Heinrich P. C., Rose-John S. The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol. 1993 Feb;23(2):473–480. doi: 10.1002/eji.1830230226. [DOI] [PubMed] [Google Scholar]
  19. Novick D., Engelmann H., Revel M., Leitner O., Rubinstein M. Monoclonal antibodies to the soluble human IL-6 receptor: affinity purification, ELISA, and inhibition of ligand binding. Hybridoma. 1991 Feb;10(1):137–146. doi: 10.1089/hyb.1991.10.137. [DOI] [PubMed] [Google Scholar]
  20. Novick D., Engelmann H., Wallach D., Leitner O., Revel M., Rubinstein M. Purification of soluble cytokine receptors from normal human urine by ligand-affinity and immunoaffinity chromatography. J Chromatogr. 1990 Jun 27;510:331–337. doi: 10.1016/s0021-9673(01)93767-7. [DOI] [PubMed] [Google Scholar]
  21. Novick D., Engelmann H., Wallach D., Rubinstein M. Soluble cytokine receptors are present in normal human urine. J Exp Med. 1989 Oct 1;170(4):1409–1414. doi: 10.1084/jem.170.4.1409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Novick D., Eshhar Z., Revel M., Mory Y. Monoclonal antibodies for affinity purification of IL-6/IFN- beta 2 and for neutralization of HGF activity. Hybridoma. 1989 Oct;8(5):561–567. doi: 10.1089/hyb.1989.8.561. [DOI] [PubMed] [Google Scholar]
  23. Portier M., Lees D., Caron E., Jourdan M., Boiron J. M., Bataille R., Klein B. Up-regulation of interleukin (IL)-6 receptor gene expression in vitro and in vivo in IL-6 deprived myeloma cells. FEBS Lett. 1992 May 4;302(1):35–38. doi: 10.1016/0014-5793(92)80278-o. [DOI] [PubMed] [Google Scholar]
  24. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  25. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278. doi: 10.1146/annurev.iy.08.040190.001345. [DOI] [PubMed] [Google Scholar]
  26. Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B., Taniguchi T., Hirano T., Kishimoto T. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988 Aug 12;241(4867):825–828. doi: 10.1126/science.3136546. [DOI] [PubMed] [Google Scholar]
  27. Yasukawa K., Saito T., Fukunaga T., Sekimori Y., Koishihara Y., Fukui H., Ohsugi Y., Matsuda T., Yawata H., Hirano T. Purification and characterization of soluble human IL-6 receptor expressed in CHO cells. J Biochem. 1990 Oct;108(4):673–676. doi: 10.1093/oxfordjournals.jbchem.a123261. [DOI] [PubMed] [Google Scholar]
  28. Yawata H., Yasukawa K., Natsuka S., Murakami M., Yamasaki K., Hibi M., Taga T., Kishimoto T. Structure-function analysis of human IL-6 receptor: dissociation of amino acid residues required for IL-6-binding and for IL-6 signal transduction through gp130. EMBO J. 1993 Apr;12(4):1705–1712. doi: 10.1002/j.1460-2075.1993.tb05815.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. de Benedetti F., Massa M., Robbioni P., Ravelli A., Burgio G. R., Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991 Sep;34(9):1158–1163. doi: 10.1002/art.1780340912. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES