Skip to main content
PMC home page
Mediators of Inflammation logoLink to Mediators of Inflammation
. 1998;7(5):347–353. doi: 10.1080/09629359890875

Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis.

T Robak 1, A Gladalska 1, H Stepień 1, E Robak 1
PMCID: PMC1781865  PMID: 9883970

Abstract

We investigated the serum concentrations of interleukin-6 (IL-6) and two IL-6 family of cytokines (leukaemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) as well as IL-6 soluble receptor (sIL-6R) using an enzyme-linked immunosorbent assay (ELISA) in 66 patients with rheumatoid arthritis (RA) and 24 healthy controls. We examined a possible association between the serum levels of these peptides and RA activity according to the Mallya and Mace scoring system and Ritchie's index. We also evaluated the correlation between the serum levels of IL-6, LIF, CNTF and sIL-6R and duration of the disease and calculated sIL-6R/IL-6 ratio in RA patients and in the control group. IL-6 and sIL-6R were detectable in all 66 patients with RA and 24 normal individuals. LIF was also found in the serum of all patients with RA and in 16 (66.7%) normal individuals. In contrast CNTF was measurable only in 15 (22.7%) patients with RA and 24 (33.3%) normal individuals. The highest IL-6 and sIL-6R levels were found in the patients with Stages 3 and 4 of RA activity and the lowest in the control group. In contrast there were no statistically significant differences between the LIF and CNTF levels in RA patients and normal individuals. We found positive correlation between IL-6 and sIL-6R concentrations and Ritchie's index and a lack of such correlation with LIF and CNTF. IL-6 serum level correlated positively with the disease duration, but sIL-6R, LIF and CNTF did not. Serum sIL-6R/IL-6 ratio was significantly lower in RA patients than in healthy controls. In conclusion, an increase in the serum levels of IL-6 and sIL-6R, but not LIF and CNTF concentrations, may be useful markers for RA activity.

Full Text

The Full Text of this article is available as a PDF (209.0 KB).

Selected References

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

  1. Akira S., Taga T., Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1–78. doi: 10.1016/s0065-2776(08)60532-5. [DOI] [PubMed] [Google Scholar]
  2. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  3. Bauer J., Herrmann F. Interleukin-6 in clinical medicine. Ann Hematol. 1991 Jun;62(6):203–210. doi: 10.1007/BF01729833. [DOI] [PubMed] [Google Scholar]
  4. Brennan F. M., Maini R. N., Feldmann M. Cytokine expression in chronic inflammatory disease. Br Med Bull. 1995 Apr;51(2):368–384. doi: 10.1093/oxfordjournals.bmb.a072967. [DOI] [PubMed] [Google Scholar]
  5. Brozik M., Rosztóczy I., Merétey K., Bálint G., Gaál M., Balogh Z., Bart M., Mituszova M., Velics V., Falus A. Interleukin 6 levels in synovial fluids of patients with different arthritides: correlation with local IgM rheumatoid factor and systemic acute phase protein production. J Rheumatol. 1992 Jan;19(1):63–68. [PubMed] [Google Scholar]
  6. De Benedetti F., Massa M., Pignatti P., Albani S., Novick D., Martini A. Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest. 1994 May;93(5):2114–2119. doi: 10.1172/JCI117206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Desgeorges A., Gabay C., Silacci P., Novick D., Roux-Lombard P., Grau G., Dayer J. M., Vischer T., Guerne P. A. Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid. J Rheumatol. 1997 Aug;24(8):1510–1516. [PubMed] [Google Scholar]
  8. Fixe P., Lorgeot V., Le Meur Y., Coupey L., Heymann D., Godard A., Praloran V. Development of enzymo-immunoassays (EIA) for macrophage colony-stimulating factor (M-CSF) and leukaemia inhibitory factor (LIF) by using the same capture and signal generating polyclonal antibody. Cytokine. 1996 Jul;8(7):586–591. doi: 10.1006/cyto.1996.0078. [DOI] [PubMed] [Google Scholar]
  9. Gabay C., Singwe M., Genin B., Meyer O., Mentha G., LeCoultre C., Vischer T., Guerne P. A. Circulating levels of IL-11 and leukaemia inhibitory factor (LIF) do not significantly participate in the production of acute-phase proteins by the liver. Clin Exp Immunol. 1996 Aug;105(2):260–265. doi: 10.1046/j.1365-2249.1996.d01-757.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Hawley R. G. Hematopathology of interleukin 6-type cytokines. Stem Cells. 1994;12 (Suppl 1):155–171. [PubMed] [Google Scholar]
  12. Heaney M. L., Golde D. W. Soluble cytokine receptors. Blood. 1996 Feb 1;87(3):847–857. [PubMed] [Google Scholar]
  13. Holt I., Cooper R. G., Denton J., Meager A., Hopkins S. J. Cytokine inter-relationships and their association with disease activity in arthritis. Br J Rheumatol. 1992 Nov;31(11):725–733. doi: 10.1093/rheumatology/31.11.725. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Hui W., Bell M., Carroll G. Detection of oncostatin M in synovial fluid from patients with rheumatoid arthritis. Ann Rheum Dis. 1997 Mar;56(3):184–187. doi: 10.1136/ard.56.3.184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Huntington T. W., Allen H. W. Dr. Camillus Bush. Memorial Exercises Held by the California Academy of Medicine, June 28, 1910. Cal State J Med. 1910 Aug;8(8):280–281. [PMC free article] [PubMed] [Google Scholar]
  17. Ivashkiv L. B. Cytokine expression and cell activation in inflammatory arthritis. Adv Immunol. 1996;63:337–376. doi: 10.1016/s0065-2776(08)60859-7. [DOI] [PubMed] [Google Scholar]
  18. Kishimoto T., Akira S., Narazaki M., Taga T. Interleukin-6 family of cytokines and gp130. Blood. 1995 Aug 15;86(4):1243–1254. [PubMed] [Google Scholar]
  19. Klareskog L., Rönnelid J., Holm G. Immunopathogenesis and immunotherapy in rheumatoid arthritis: an area in transition. J Intern Med. 1995 Sep;238(3):191–206. doi: 10.1111/j.1365-2796.1995.tb00923.x. [DOI] [PubMed] [Google Scholar]
  20. Koch A. E., Kunkel S. L., Strieter R. M. Cytokines in rheumatoid arthritis. J Investig Med. 1995 Feb;43(1):28–38. [PubMed] [Google Scholar]
  21. Kotake S., Sato K., Kim K. J., Takahashi N., Udagawa N., Nakamura I., Yamaguchi A., Kishimoto T., Suda T., Kashiwazaki S. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res. 1996 Jan;11(1):88–95. doi: 10.1002/jbmr.5650110113. [DOI] [PubMed] [Google Scholar]
  22. Le J. M., Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest. 1989 Dec;61(6):588–602. [PubMed] [Google Scholar]
  23. Lorgeot V., Praloran V., Turlure P., Denizot Y. Concentrations of serum leukemia inhibitory factor (LIF) in patients with hematologic malignancies. Leukemia. 1997 Feb;11(2):311–312. doi: 10.1038/sj.leu.2400570. [DOI] [PubMed] [Google Scholar]
  24. Lotz M., Moats T., Villiger P. M. Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. J Clin Invest. 1992 Sep;90(3):888–896. doi: 10.1172/JCI115964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mackiewicz A., Schooltink H., Heinrich P. C., Rose-John S. Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. J Immunol. 1992 Sep 15;149(6):2021–2027. [PubMed] [Google Scholar]
  26. Madhok R., Crilly A., Watson J., Capell H. A. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis. 1993 Mar;52(3):232–234. doi: 10.1136/ard.52.3.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mallya R. K., Mace B. E. The assessment of disease activity in rheumatoid arthritis using a multivariate analysis. Rheumatol Rehabil. 1981 Feb 1;20(1):14–17. doi: 10.1093/rheumatology/20.1.14. [DOI] [PubMed] [Google Scholar]
  28. Mihara M., Moriya Y., Kishimoto T., Ohsugi Y. Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor. Br J Rheumatol. 1995 Apr;34(4):321–325. doi: 10.1093/rheumatology/34.4.321. [DOI] [PubMed] [Google Scholar]
  29. Okamoto H., Yamamura M., Morita Y., Harada S., Makino H., Ota Z. The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis Rheum. 1997 Jun;40(6):1096–1105. doi: 10.1002/art.1780400614. [DOI] [PubMed] [Google Scholar]
  30. Peters M., Meyer zum Büschenfelde K. H., Rose-John S. The function of the soluble IL-6 receptor in vivo. Immunol Lett. 1996 Dec;54(2-3):177–184. doi: 10.1016/s0165-2478(96)02669-7. [DOI] [PubMed] [Google Scholar]
  31. ROPES M. W., BENNETT G. A., COBB S., JACOX R., JESSAR R. A. 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis. 1958 Dec;9(4):175–176. [PubMed] [Google Scholar]
  32. Ritchie D. M., Boyle J. A., McInnes J. M., Jasani M. K., Dalakos T. G., Grieveson P., Buchanan W. W. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med. 1968 Jul;37(147):393–406. [PubMed] [Google Scholar]
  33. Robak E., Sysa-Jedrzejowska A., Stepień H., Robak T. Circulating interleukin-6 type cytokines in patients with systemic lupus erythematosus. Eur Cytokine Netw. 1997 Sep;8(3):281–286. [PubMed] [Google Scholar]
  34. Robak T., Gladalska A., Stepień H. The tumour necrosis factor family of receptors/ligands in the serum of patients with rheumatoid arthritis. Eur Cytokine Netw. 1998 Jun;9(2):145–154. [PubMed] [Google Scholar]
  35. Robinson R. C., Grey L. M., Staunton D., Vankelecom H., Vernallis A. B., Moreau J. F., Stuart D. I., Heath J. K., Jones E. Y. The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding. Cell. 1994 Jul 1;77(7):1101–1116. doi: 10.1016/0092-8674(94)90449-9. [DOI] [PubMed] [Google Scholar]
  36. Rönnelid J., Berg L., Rogberg S., Nilsson A., Albertsson K., Klareskog L. Production of T-cell cytokines at the single-cell level in patients with inflammatory arthritides: enhanced activity in synovial fluid compared to blood. Br J Rheumatol. 1998 Jan;37(1):7–14. doi: 10.1093/rheumatology/37.1.7. [DOI] [PubMed] [Google Scholar]
  37. Simpson R. J., Hammacher A., Smith D. K., Matthews J. M., Ward L. D. Interleukin-6: structure-function relationships. Protein Sci. 1997 May;6(5):929–955. doi: 10.1002/pro.5560060501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Smith S. R., Morgan L. Soluble IL-6R in plasma cell dyscrasias. Leuk Lymphoma. 1997 Aug;26(5-6):489–495. doi: 10.3109/10428199709050885. [DOI] [PubMed] [Google Scholar]
  39. Waring P. M., Carroll G. J., Kandiah D. A., Buirski G., Metcalf D. Increased levels of leukemia inhibitory factor in synovial fluid from patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1993 Jul;36(7):911–915. doi: 10.1002/art.1780360707. [DOI] [PubMed] [Google Scholar]
  40. Waring P., Wycherley K., Cary D., Nicola N., Metcalf D. Leukemia inhibitory factor levels are elevated in septic shock and various inflammatory body fluids. J Clin Invest. 1992 Nov;90(5):2031–2037. doi: 10.1172/JCI116083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wendling D., Racadot E., Wijdenes J. Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J Rheumatol. 1993 Feb;20(2):259–262. [PubMed] [Google Scholar]
  42. Weyand C. M., Goronzy J. J. Pathogenesis of rheumatoid arthritis. Med Clin North Am. 1997 Jan;81(1):29–55. doi: 10.1016/s0025-7125(05)70504-6. [DOI] [PubMed] [Google Scholar]
  43. Yasukawa K., Futatsugi K., Saito T., Yawata H., Narazaki M., Suzuki H., Taga T., Kishimoto T. Association of recombinant soluble IL-6-signal transducer, gp130, with a complex of IL 6 and soluble IL-6 receptor, and establishment of an ELISA for soluble gp130. Immunol Lett. 1992 Feb;31(2):123–130. doi: 10.1016/0165-2478(92)90138-e. [DOI] [PubMed] [Google Scholar]
  44. van Leeuwen M. A., Westra J., Limburg P. C., van Riel P. L., van Rijswijk M. H. Clinical significance of interleukin-6 measurement in early rheumatoid arthritis: relation with laboratory and clinical variables and radiological progression in a three year prospective study. Ann Rheum Dis. 1995 Aug;54(8):674–677. doi: 10.1136/ard.54.8.674. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES