Skip to main content

Advertisement

SpringerLink
Log in

Serum Pro-hepcidin Levels in Rheumatoid Arthritis and Systemic Lupus Erythematosus

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Hepcidin is a principal iron regulatory hormone and its expression is stimulated by cytokines. The aim of this study was to determine serum levels of the prohormone form of hepcidin, pro-hepcidin, in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The study included 72 RA and 28 SLE patients and 33 healthy controls (HC). Serum iron status, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and pro-hepcidin levels were determined. Pro-hepcidin levels in the RA group was higher than SLE and HC groups (p < 0.05, p < 0.001, respectively). Pro-hepcidin levels did not correlate with disease activity scores, cytokine levels and serum iron status in the RA and SLE groups, while it correlated with TNF-α, IL-6 and ferritin levels in the HC group (r = 0.459, p < 0.01, r = 0.374, p < 0.05, r = −0.603, p < 0.01, respectively). Pro-hepcidin levels show extremely wide variations within the groups as do iron status and cytokines. Despite these wide variations correlation analysis do not reveal anything.

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

Similar content being viewed by others

References

  1. Means, R. T., and S. B. Krantz. 1992. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 80:1639–1647.

    PubMed  Google Scholar 

  2. Means, R. T. 1999. Advances in the anemia of chronic disease. Int. J. Hematol. 70:7–12.

    PubMed  Google Scholar 

  3. Weiss, G., and L. T. Goodnough. 2005. Anemia of chronic disease. N. Engl. J. Med. 352:1011–1023.

    Article  PubMed  CAS  Google Scholar 

  4. Das Gupta, A., and A. Abbi. 2003. High serum transferrin receptor level in anemia of chronic disorders indicates coexistent iron deficiency. Am. J. Hematol. 72:158–161.

    Article  PubMed  CAS  Google Scholar 

  5. Alvarez-Hernandez, X., J. Liceaga, I. C. McKay, and J. H. Brock. 1989. Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor. Lab. Invest. 61:319–322.

    PubMed  CAS  Google Scholar 

  6. Moldawer, L. L., M. A. Marano, H. Wei, Y. Fong, M. L. Silen, G. Kuo, K. R. Manogue, H. Vlassara, H. Cohen, A. Cerami, and S. F. Lowry. 1989. Cachectin/tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo. FASEB J. 3:1637–1643.

    PubMed  CAS  Google Scholar 

  7. Faquin, W. C., T. J. Schneider, and M. A. Goldberg. 1992. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood 79:1987–1894.

    PubMed  CAS  Google Scholar 

  8. Papadaki, H. A., H. D. Kritikos, V. Valatas, D. T. Boumpas, and G. D. Eliopoulos. 2002. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood 100:474–482.

    Article  PubMed  CAS  Google Scholar 

  9. Torti, F. M., and S. V. Torti. 2002. Regulation of ferritin genes and protein. Blood 99:3505–3516.

    Article  PubMed  CAS  Google Scholar 

  10. Maury, C. P., L. C. Andersson, A. M. Teppo, S. Partanen, and E. Juvonen. 1988. Mechanism of anaemia in rheumatoid arthritis: demonstration of raised interleukin 1 beta concentrations in anaemic patients and of interleukin 1 mediated suppression of normal erythropoiesis and proliferation of human erythroleukaemia (HEL) cells in vitro. Ann. Rheum. Dis. 47:972–978.

    Article  PubMed  CAS  Google Scholar 

  11. Nemeth, E., M. S. Tuttle, J. Powelson, M. B. Vaughn, A. Donovan, D. M. Ward, T. Ganz, and J. Kaplan. 2004. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093.

    Article  PubMed  CAS  Google Scholar 

  12. Nemeth, E., S. Rivera, V. Gabayan, C. Keller, S. Taudorf, B. K. Pedersen, and T. Ganz. 2004. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113:1271–1276.

    PubMed  CAS  Google Scholar 

  13. Pigeon, C., G. Ilyin, B. Courselaud, P. Leroyer, B. Turlin, P. Brissot, and O. Loreal. 2001. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J. Biol. Chem. 276:7811–7819.

    Article  PubMed  CAS  Google Scholar 

  14. Nicolas, G., C. Chauvet, L. Viatte, J. L. Danan, X. Bigard, I. Devaux, C. Beaumont, A. Kahn, and S. Vaulont. 2002. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110:1037–1044.

    PubMed  CAS  Google Scholar 

  15. Nemeth, E., E. V. Valore, M. Territo, G. Schiller, A. Lichtenstein, and T. Ganz. 2003. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101:2461–2463.

    Article  PubMed  CAS  Google Scholar 

  16. Vyoral, D., and J. Petrak. 2005. Hepcidin: a direct link between iron metabolism and immunity. Int. J. Biochem. Cell Biol. 37:1768–1773.

    Article  PubMed  CAS  Google Scholar 

  17. Tomosugi, N., H. Kawabata, R. Wakatabe, M. Higuchi, H. Yamaya, H. Umehara, and I. Ishikawa. 2006. Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System(R). Blood 108:1381–1387.

    Article  PubMed  CAS  Google Scholar 

  18. Kulaksiz, H., S. G. Gehrke, A. Janetzko, D. Rost, T. Bruckner, B. Kallinowski, and W. Stremmel. 2004. Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia. Gut. 53:735–743.

    Article  PubMed  CAS  Google Scholar 

  19. Kemna, E., H. Tjalsma, C. Laarakkers, E. Nemeth, H. Willems, and D. Swinkels. 2005. Novel urine hepcidin assay by mass spectrometry. Blood 106:3268–3270.

    Article  PubMed  CAS  Google Scholar 

  20. Arnett, F. C., S. M. Edworthy, D. A. Bloch, D. J. McShane, J. F. Fries, N. S. Cooper, L. A. Healey, S. R. Kaplan, et al. 1988. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31:315–324.

    Article  PubMed  CAS  Google Scholar 

  21. Hochberg, M. C. 1997. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40:1725.

    Article  PubMed  CAS  Google Scholar 

  22. Leeb, B. F., I. Andel, J. Sautner, M. Bogdan, A. Maktari, T. Nothnagl, and B. Rintelen. 2005. Disease activity measurement of rheumatoid arthritis: Comparison of the simplified disease activity index (SDAI) and the disease activity score including 28 joints (DAS28) in daily routine. Arthritis Rheum. 53:56–60.

    Article  PubMed  Google Scholar 

  23. Bombardier, C., D. D. Gladman, M. B. Urowitz, D. Caron, and C. H. Chang. 1992. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 35:630–640.

    Article  PubMed  CAS  Google Scholar 

  24. Kulaksiz, H., F. Theilig, S. Bachmann, S. G. Gehrke, D. Rost, A. Janetzko, Y. Cetin, and W. Stremmel. 2005. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J. Endocrinol. 184:361–370.

    Article  PubMed  CAS  Google Scholar 

  25. Giannouli, S., M. Voulgarelis, P. D. Ziakas, and A. G. Tzioufas. 2006. Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment. Ann. Rheum. Dis. 65:144–148.

    Article  PubMed  CAS  Google Scholar 

  26. Glossop, J. R., P. T. Dawes, A. B. Hassell, and D. L. Mattey. 2005. Anemia in rheumatoid arthritis: association with polymorphism in the tumor necrosis factor receptor I and II genes. J. Rheumatol. 32:1673–1678.

    PubMed  CAS  Google Scholar 

  27. Hansen, T. M., N. E. Hansen, H. S. Birgens, B. Holund, and I. Lorenzen. 1983. Serum ferritin and the assessment of iron deficiency in rheumatoid arthritis. Scand. J. Rheumatol. 12:353–359.

    Article  PubMed  CAS  Google Scholar 

  28. Lee, P., H. Peng, T. Gelbart, L. Wang, and E. Beutler. 2005. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc. Natl. Acad. Sci. U. S. A. 102:1906–1910.

    Article  PubMed  CAS  Google Scholar 

  29. Keeling, D. M., and D. A. Isenberg. 1993. Haematological manifestations of systemic lupus erythematosus. Blood Rev. 7:199–207.

    Article  PubMed  CAS  Google Scholar 

  30. Canete, J. D., S. E. Martinez, J. Farres, R. Sanmarti, M. Blay, A. Gomez, G. Salvador, and J. Munoz-Gomez. 2000. Differential Th1/Th2 cytokine patterns in chronic arthritis: interferon gamma is highly expressed in synovium of rheumatoid arthritis compared with seronegative spondyloarthropathies. Ann. Rheum. Dis. 59:263–268.

    Article  PubMed  CAS  Google Scholar 

  31. Hagiwara, E. N., M. F. Gourley, S. Lee, and D. M. Klinman. 1996. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of Interleukin-10: Interferon-γ secreting cells in the peripheral blood. Arthritis Rheum. 39:379–385.

    Article  PubMed  CAS  Google Scholar 

  32. Malyszko, J., J. S. Malyszko, T. Hryszko, K. Pawlak, and M. Mysliwiec. 2005. Is hepcidin a link between anemia, inflammation and liver function in hemodialyzed patients? Am. J. Nephrol. 25:586–590.

    Article  PubMed  CAS  Google Scholar 

  33. Vreugdenhil, G., B. Lowenberg, H. G. Van Eijk, and A. J. Swaak. 1992. Tumor necrosis factor alpha is associated with disease activity and the degree of anemia in patients with rheumatoid arthritis. Eur. J. Clin. Invest. 22:488–493.

    Article  PubMed  CAS  Google Scholar 

  34. Roodman, G. D., R. A. Johnson, and U. Clibon. 1989. Tumor necrosis factor alpha and the anemia of chronic disease: effects of chronic exposure to TNF on erythropoiesis in vivo. Adv. Exp. Med. Biol. 271:185–196.

    PubMed  CAS  Google Scholar 

  35. Jongen-Lavrencic, M., H. R. Peeters, B. Backx, I. P. Touw, G. Vreugdenhil, and A. J. Swaak. 1994. R-h-erythropoietin counteracts the inhibition of in vitro erythropoiesis by tumour necrosis factor alpha in patients with rheumatoid arthritis. Rheumatol. Int. 14:109–113.

    Article  PubMed  CAS  Google Scholar 

  36. Theurl, I., V. Mattle, M. Seifert, M. Mariani, C. Marth, and G. Weiss. 2006. Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. Blood 107:4142–4148.

    Article  PubMed  CAS  Google Scholar 

  37. Dallalio, G., T. Fleury, and R. T. Means. 2003. Serum hepcidin in clinical specimens. Br. J. Haematol. 122:996–1000.

    Article  PubMed  CAS  Google Scholar 

  38. Nagashima, M., M. Kudo, H. Chung, E. Ishikawa, S. Hagiwara, T. Nakatani, and K. Dote. 2006. Regulatory failure of serum prohepcidin levels in patients with hepatitis C. Hepatol. Res. 36:288–293.

    Article  PubMed  CAS  Google Scholar 

  39. Taes, Y. E., B. Wuyts, J. R. Boelaert, A. S. De Vriese, and J. R. Delanghe. 2004. Prohepcidin accumulates in renal insufficiency. Clin. Chem. Lab. Med. 42:387–389.

    Article  PubMed  CAS  Google Scholar 

  40. Roe, M. A., C. Spinks, A. L. Heath, L. J. Harvey, R. Foxall, J. Wimperis, C. Wolf, and S. J. Fairweather-Tait. 2007. Serum prohepcidin concentration: no association with iron absorption in healthy men; and no relationship with iron status in men carrying HFE mutations, hereditary haemochromatosis patients undergoing phlebotomy treatment, or pregnant women. Br. J. Nutr. 97:544–549.

    Article  PubMed  CAS  Google Scholar 

  41. Feldmann, M., F. M. Brennan, and R. N. Maini. 1996. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14:397–440.

    Article  PubMed  CAS  Google Scholar 

  42. Bridges, S. L., and A. Davidson. 2005. Rheumatoid factor. In: Arthritis and allied conditions a textbook of rheumatology, Koppman, W. J., and L. W. Moreland eds. 15th ed. Lippincot Williams and Wilkins, Philadelphia, pp. 1227–1247.

    Google Scholar 

Download references

Acknowledgement

We thank to Mr. Cihangir Kosu and Mr. Kamil M. Atmis from Abbott Turkey for their grateful contributions.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Faculty of Medicine, Firat University, Elazig, Turkey

    Suleyman Serdar Koca, Ahmet Isik & Kader Aksoy

  2. Department of Biochemistry, Faculty of Medicine, Firat University, Elazig, Turkey

    Bilal Ustundag & Kerem Metin

  3. Firat University, Firat Tip Merkezi, İc Hastaliklari ABD./Romatoloji BD., 23119, Elazig, Turkey

    Suleyman Serdar Koca

Authors
  1. Suleyman Serdar Koca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmet Isik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bilal Ustundag
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kerem Metin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kader Aksoy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suleyman Serdar Koca.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koca, S.S., Isik, A., Ustundag, B. et al. Serum Pro-hepcidin Levels in Rheumatoid Arthritis and Systemic Lupus Erythematosus. Inflammation 31, 146–153 (2008). https://doi.org/10.1007/s10753-008-9060-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-008-9060-8

Key words

Search

Navigation