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Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2005 Jun;64(6):849–853. doi: 10.1136/ard.2004.022681

Raised levels of interleukin 6 in systemic lupus erythematosus correlate with anaemia

B Ripley 1, B Goncalves 1, D Isenberg 1, D Latchman 1, A Rahman 1
PMCID: PMC1755543  PMID: 15897306

Abstract

Objectives: Raised levels of the cytokines interleukin (IL) 6 and IL10 have been reported in patients with systemic lupus erythematosus (SLE).

Objective: To determine if levels of IL6 and IL10 correlate with organ/system-specific disease activity in SLE, using the British Isles Lupus Assessment Group (BILAG) Disease Activity Index.

Methods: Levels of IL6 and IL10 in serum samples from 171 patients with SLE and 50 normal controls were determined by enzyme linked immunosorbent assay (ELISA). Levels of cytokines in individual patients with SLE were compared with the presence or absence of active disease in eight organ/systems using the BILAG index.

Results: Levels of IL6 were significantly higher (p = 0.005) in patients with active compared with inactive haematological disease, as scored by the BILAG index. Further analysis showed that this association was dependent on an inverse correlation (p = 0.002, r = –0.26) between IL6 levels and haemoglobin levels in patients with SLE. In contrast, IL10 levels did not correlate with individual organ/system disease activity.

Conclusions: Raised levels of IL6 in SLE may influence the development of anaemia in this disease. These findings are in agreement with an increasing number of studies, which support physiological links between IL6 and anaemia. Importantly, with the exception of the haematological system, our studies do not provide evidence of any individual organ/system which would respond to therapeutic manipulation of either IL6 or IL10 levels.

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Figure 1.

Figure 1

 Bar charts representing levels of (A) IL6 and (B) IL10 in patients with SLE graded by the BILAG index. Error bars represent 95% confidence intervals for the mean. CON, constitutional; MUC, mucocutaneous; CNS, central nervous system; MUSC, musculoskeletal; CV, cardiovascular; VASC, vasculitis; RENAL, renal; HAEM, haematological.

Figure 2.

Figure 2

 Scattergraph comparing levels of IL6 and haemoglobin in individual patients with SLE. A trendline and associated Pearson correlation coefficient (r) and p value are shown.

Figure 3.

Figure 3

 Mean levels of IL6 in patients with or without anaemia. Error bars represent 95% confidence intervals for the mean. The p value represents significance of difference in mean values as determined by Student's t test for equality of means.

Selected References

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

  1. Andus T., Geiger T., Hirano T., Northoff H., Ganter U., Bauer J., Kishimoto T., Heinrich P. C. Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-beta 2) regulates beta-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 1987 Aug 31;221(1):18–22. doi: 10.1016/0014-5793(87)80344-7. [DOI] [PubMed] [Google Scholar]
  2. Dhillon V. B., McCallum S., Latchman D. S., Isenberg D. A. Elevation of the 90 kDa heat-shock protein in specific subsets of systemic lupus erythematosus. Q J Med. 1994 Apr;87(4):215–222. [PubMed] [Google Scholar]
  3. Ershler W. B., Keller E. T. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245–270. doi: 10.1146/annurev.med.51.1.245. [DOI] [PubMed] [Google Scholar]
  4. Ershler William B. Biological interactions of aging and anemia: a focus on cytokines. J Am Geriatr Soc. 2003 Mar;51(3 Suppl):S18–S21. doi: 10.1046/j.1532-5415.51.3s.2.x. [DOI] [PubMed] [Google Scholar]
  5. Faquin W. C., Schneider T. J., Goldberg M. A. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood. 1992 Apr 15;79(8):1987–1994. [PubMed] [Google Scholar]
  6. Gröndal G., Gunnarsson I., Rönnelid J., Rogberg S., Klareskog L., Lundberg I. Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol. 2000 Sep-Oct;18(5):565–570. [PubMed] [Google Scholar]
  7. Hagiwara E., Gourley M. F., Lee S., Klinman D. K. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10:interferon-gamma-secreting cells in the peripheral blood. Arthritis Rheum. 1996 Mar;39(3):379–385. doi: 10.1002/art.1780390305. [DOI] [PubMed] [Google Scholar]
  8. Hay E. M., Bacon P. A., Gordon C., Isenberg D. A., Maddison P., Snaith M. L., Symmons D. P., Viner N., Zoma A. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q J Med. 1993 Jul;86(7):447–458. [PubMed] [Google Scholar]
  9. Hochberg M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725–1725. doi: 10.1002/art.1780400928. [DOI] [PubMed] [Google Scholar]
  10. Ishida H., Muchamuel T., Sakaguchi S., Andrade S., Menon S., Howard M. Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med. 1994 Jan 1;179(1):305–310. doi: 10.1084/jem.179.1.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jason J., Archibald L. K., Nwanyanwu O. C., Bell M., Jensen R. J., Gunter E., Buchanan I., Larned J., Kazembe P. N., Dobbie H. The effects of iron deficiency on lymphocyte cytokine production and activation: preservation of hepatic iron but not at all cost. Clin Exp Immunol. 2001 Dec;126(3):466–473. doi: 10.1046/j.1365-2249.2001.01707.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kishimoto T., Hirano T. A new interleukin with pleiotropic activities. Bioessays. 1988 Jul;9(1):11–15. doi: 10.1002/bies.950090104. [DOI] [PubMed] [Google Scholar]
  13. Klashman D. J., Martin R. A., Martínez-Maza O., Stevens R. H. In vitro regulation of B cell differentiation by interleukin-6 and soluble CD23 in systemic lupus erythematosus B cell subpopulations and antigen-induced normal B cells. Arthritis Rheum. 1991 Mar;34(3):276–286. doi: 10.1002/art.1780340305. [DOI] [PubMed] [Google Scholar]
  14. Kurihara N., Bertolini D., Suda T., Akiyama Y., Roodman G. D. IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release. J Immunol. 1990 Jun 1;144(11):4226–4230. [PubMed] [Google Scholar]
  15. Leng H. M., Kidson S. H., Keraan M. M., Randall G. W., Folb P. I. Cytokine-mediated inhibition of erythropoietin synthesis by dexamethasone. J Pharm Pharmacol. 1996 Sep;48(9):971–974. doi: 10.1111/j.2042-7158.1996.tb06015.x. [DOI] [PubMed] [Google Scholar]
  16. Leng Sean, Chaves Paulo, Koenig Kathleen, Walston Jeremy. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc. 2002 Jul;50(7):1268–1271. doi: 10.1046/j.1532-5415.2002.50315.x. [DOI] [PubMed] [Google Scholar]
  17. Levy Y., Brouet J. C. Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest. 1994 Jan;93(1):424–428. doi: 10.1172/JCI116977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Linker-Israeli M., Deans R. J., Wallace D. J., Prehn J., Ozeri-Chen T., Klinenberg J. R. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol. 1991 Jul 1;147(1):117–123. [PubMed] [Google Scholar]
  19. Llorente L., Richaud-Patin Y., García-Padilla C., Claret E., Jakez-Ocampo J., Cardiel M. H., Alcocer-Varela J., Grangeot-Keros L., Alarcón-Segovia D., Wijdenes J. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum. 2000 Aug;43(8):1790–1800. doi: 10.1002/1529-0131(200008)43:8<1790::AID-ANR15>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  20. Llorente L., Richaud-Patin Y., Wijdenes J., Alcocer-Varela J., Maillot M. C., Durand-Gasselin I., Fourrier B. M., Galanaud P., Emilie D. Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus. Eur Cytokine Netw. 1993 Nov-Dec;4(6):421–427. [PubMed] [Google Scholar]
  21. Llorente L., Zou W., Levy Y., Richaud-Patin Y., Wijdenes J., Alcocer-Varela J., Morel-Fourrier B., Brouet J. C., Alarcon-Segovia D., Galanaud P. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med. 1995 Mar 1;181(3):839–844. doi: 10.1084/jem.181.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Moore K. W., de Waal Malefyt R., Coffman R. L., O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765. doi: 10.1146/annurev.immunol.19.1.683. [DOI] [PubMed] [Google Scholar]
  23. Nieken J., Mulder N. H., Buter J., Vellenga E., Limburg P. C., Piers D. A., de Vries E. G. Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients. Blood. 1995 Aug 1;86(3):900–905. [PubMed] [Google Scholar]
  24. Park Y. B., Lee S. K., Kim D. S., Lee J., Lee C. H., Song C. H. Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol. 1998 May-Jun;16(3):283–288. [PubMed] [Google Scholar]
  25. Ripley B. J., Isenberg D. A., Latchman D. S. Elevated levels of the 90 kDa heat shock protein (hsp90) in SLE correlate with levels of IL-6 and autoantibodies to hsp90. J Autoimmun. 2001 Dec;17(4):341–346. doi: 10.1006/jaut.2001.0549. [DOI] [PubMed] [Google Scholar]
  26. Satoh T., Nakamura S., Taga T., Matsuda T., Hirano T., Kishimoto T., Kaziro Y. Induction of neuronal differentiation in PC12 cells by B-cell stimulatory factor 2/interleukin 6. Mol Cell Biol. 1988 Aug;8(8):3546–3549. doi: 10.1128/mcb.8.8.3546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Spronk P. E., ter Borg E. J., Limburg P. C., Kallenberg C. G. Plasma concentration of IL-6 in systemic lupus erythematosus; an indicator of disease activity? Clin Exp Immunol. 1992 Oct;90(1):106–110. doi: 10.1111/j.1365-2249.1992.tb05840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sun W. H., Binkley N., Bidwell D. W., Ershler W. B. The influence of recombinant human interleukin-6 on blood and immune parameters in middle-aged and old rhesus monkeys. Lymphokine Cytokine Res. 1993 Dec;12(6):449–455. [PubMed] [Google Scholar]
  29. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]
  30. Tyrrell-Price J., Lydyard P. M., Isenberg D. A. The effect of interleukin-10 and of interleukin-12 on the in vitro production of anti-double-stranded DNA antibodies from patients with systemic lupus erythematosus. Clin Exp Immunol. 2001 Apr;124(1):118–125. doi: 10.1046/j.1365-2249.2001.01466.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Waszczykowska E., Robak E., Wozniacka A., Narbutt J., Torzecka J. D., Sysa-Jedrzejowska A. Estimation of SLE activity based on the serum level of chosen cytokines and superoxide radical generation. Mediators Inflamm. 1999;8(2):93–100. doi: 10.1080/09629359990586. [DOI] [PMC free article] [PubMed] [Google Scholar]

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