Journal of Clinical Immunology

, Volume 29, Issue 1, pp 38–45

Interleukin-18 Binding Protein in the Sera of Patients with Wegener’s Granulomatosis




In the present study, we examined the levels of the pro-inflammatory cytokine IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP), in sera of Wegener’s granulomatosis (WG) patients at various stages of the disease.

Patients and Methods

Sera from eight consecutive biopsy-proven systemic WG patients (four men and four women; age at diagnosis 58.4 ± 13.8 years) were obtained longitudinally with a follow-up period of 55.2 ± 30 months. Sera obtained from 50 healthy subjects were used as controls.

Results and Discussion

Serum levels of IL-18, IL-18BP, and free IL-18 obtained during an active phase of the disease (Birmingham Vasculitis Activity Score, BVAS > 10) were more than twofold higher than levels in the same patients during inactive disease stages (BVAS < 5; P < 0.002; P < 0.006, and P < 0.03 for IL-18, IL-18BP, and free IL-18, respectively). During inactive stages, the levels of these markers were comparable to those of healthy controls. The elevated levels of IL-18 and IL-18BP in sera during active stages of disease suggest a possible role in the pathogenesis and course of the WG.


Despite the elevated IL-18BP levels during active disease, free IL-18 remained higher than in the inactive disease stages, suggesting a potential benefit of administration of exogenous IL-18BP as a novel therapeutic approach for active WG.


ANCA inflammation PR3 cytokines 


  1. 1.
    Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488–98.PubMedGoogle Scholar
  2. 2.
    Cotch MF, Hoffman GS, Yerg DE, Kaufman GI, Targonski P, Kaslow RA. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum 1996;39:87–92. doi:10.1002/art.1780390112.PubMedCrossRefGoogle Scholar
  3. 3.
    Stone JH. Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum 2003;48:2299–309. doi:10.1002/art.11075.PubMedCrossRefGoogle Scholar
  4. 4.
    Wung PK, Stone JH. Therapeutics of Wegener’s granulomatosis. Nat Clin Pract Rheumatol 2006;2:192–200. doi:10.1038/ncprheum0139.PubMedCrossRefGoogle Scholar
  5. 5.
    Boomsma MM, Stegeman CA, van der Leij MJ, Oost W, Hermans J, Kallenberg CG, et al. Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 2000;43:2025–33. doi:10.1002/1529-0131(200009)43:9<2025::AID-ANR13>3.0.CO;2-O.PubMedCrossRefGoogle Scholar
  6. 6.
    Komocsi A, Lamprecht P, Csernok E, Mueller A, Holl-Ulrich K, Seitzer U, et al. Peripheral blood and granuloma CD4(+)CD28(−) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener’s granulomatosis. Am J Pathol 2002;160:1717–24.PubMedGoogle Scholar
  7. 7.
    Csernok E, Trabandt A, Muller A, Wang GC, Moosig F, Paulsen J, et al. Cytokine profiles in Wegener’s granulomatosis: predominance of type 1 (Th1) in the granulomatous inflammation. Arthritis Rheum 1999;42:742–50. doi:10.1002/1529-0131(199904)42:4<742::AID-ANR18>3.0.CO;2-I.PubMedCrossRefGoogle Scholar
  8. 8.
    Ludviksson BR, Sneller MC, Chua KS, Talar-Williams C, Langford CA, Ehrhardt RO, et al. Active Wegener’s granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10. J Immunol 1998;160:3602–9.PubMedGoogle Scholar
  9. 9.
    Torheim EA, Yndestad A, Bjerkeli V, Halvorsen B, Aukrust P, Froland SS. Increased expression of chemokines in patients with Wegener’s granulomatosis—modulating effects of methylprednisolone in vitro. Clin Exp Immunol 2005;140:376–83. doi:10.1111/j.1365-2249.2005.02770.x.PubMedCrossRefGoogle Scholar
  10. 10.
    Mukhtyar C, Luqmani R. Current state of tumour necrosis factor {alpha} blockade in Wegener’s granulomatosis. Ann Rheum Dis 2005;64(Suppl 4):iv31–6. doi:10.1136/ard.2005.042416.PubMedCrossRefGoogle Scholar
  11. 11.
    Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995;378:88–91. doi:10.1038/378088a0.PubMedCrossRefGoogle Scholar
  12. 12.
    Okamura H, Tsutsui H, Kashiwamura S, Yoshimoto T, Nakanishi K. Interleukin-18: a novel cytokine that augments both innate and acquired immunity. Adv Immunol 1998;70:281–312. doi:10.1016/S0065-2776(08)60389-2.PubMedCrossRefGoogle Scholar
  13. 13.
    Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol 2003;73:213–24. doi:10.1189/jlb.0602313.PubMedCrossRefGoogle Scholar
  14. 14.
    Nakamura K, Okamura H, Wada M, Nagata K, Tamura T. Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun 1989;57:590–5.PubMedGoogle Scholar
  15. 15.
    Maxwell JR, Yadav R, Rossi RJ, Ruby CE, Weinberg AD, Aguila HL, et al. IL-18 bridges innate and adaptive immunity through IFN-gamma and the CD134 pathway. J Immunol 2006;177:234–45.PubMedGoogle Scholar
  16. 16.
    Torigoe K, Ushio S, Okura T, Kobayashi S, Taniai M, Kunikata T, et al. Purification and characterization of the human interleukin-18 receptor. J Biol Chem 1997;272:25737–42. doi:10.1074/jbc.272.41.25737.PubMedCrossRefGoogle Scholar
  17. 17.
    Born TL, Thomassen E, Bird TA, Sims JE. Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling. J Biol Chem 1998;273:29445–50. doi:10.1074/jbc.273.45.29445.PubMedCrossRefGoogle Scholar
  18. 18.
    Boraschi D, Dinarello CA. IL-18 in autoimmunity. Eur Cytokine Netw 2006;17:224–52.PubMedGoogle Scholar
  19. 19.
    Wong CK, Li EK, Ho CY, Lam CW. Elevation of plasma interleukin-18 concentration is correlated with disease activity in systemic lupus erythematosus. Rheumatology (Oxford) 2000;39:1078–81. doi:10.1093/rheumatology/39.10.1078.CrossRefGoogle Scholar
  20. 20.
    Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 1999;10:127–36. doi:10.1016/S1074-7613(00)80013-8.PubMedCrossRefGoogle Scholar
  21. 21.
    Kim SH, Eisenstein M, Reznikov L, Fantuzzi G, Novick D, Rubinstein M, et al. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci U S A 2000;97:1190–5. doi:10.1073/pnas.97.3.1190.PubMedCrossRefGoogle Scholar
  22. 22.
    Hurgin V, Novick D, Rubinstein M. The promoter of IL-18 binding protein: activation by an IFN-gamma -induced complex of IFN regulatory factor 1 and CCAAT/enhancer binding protein beta. Proc Natl Acad Sci U S A 2002;99:16957–62. doi:10.1073/pnas.262663399.PubMedCrossRefGoogle Scholar
  23. 23.
    Novick D, Schwartsburd B, Pinkus R, Suissa D, Belzer I, Sthoeger Z, et al. A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Cytokine 2001;14:334–42. doi:10.1006/cyto.2001.0914.PubMedCrossRefGoogle Scholar
  24. 24.
    Ludwiczek O, Kaser A, Novick D, Dinarello CA, Rubinstein M, Tilg H. Elevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn’s disease. Eur Cytokine Netw 2005;16:27–33.PubMedGoogle Scholar
  25. 25.
    Kaser A, Novick D, Rubinstein M, Siegmund B, Enrich B, Koch RO, et al. Interferon-alpha induces interleukin-18 binding protein in chronic hepatitis C patients. Clin Exp Immunol 2002;129:332–8. doi:10.1046/j.1365-2249.2002.01911.x.PubMedCrossRefGoogle Scholar
  26. 26.
    Leach ST, Messina I, Lemberg DA, Novick D, Rubenstein M, Day AS. Local and systemic interleukin-18 and interleukin-18-binding protein in children with inflammatory bowel disease. Inflamm Bowel Dis 2008;14:68–74. doi:10.1002/ibd.20272.PubMedCrossRefGoogle Scholar
  27. 27.
    Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33:1101–7.PubMedGoogle Scholar
  28. 28.
    Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37:187–92. doi:10.1002/art.1780370206.PubMedCrossRefGoogle Scholar
  29. 29.
    Luqmani RA, Bacon PA, Beaman M, Scott DG, Emery P, Lee SJ, et al. Classical versus non-renal Wegener’s granulomatosis. Q J Med 1994;87:671–8.Google Scholar
  30. 30.
    Gatto-Menking DL, Yu H, Bruno JG, Goode MT, Miller M, Zulich AW. Sensitive detection of biotoxoids and bacterial spores using an immunomagnetic electrochemiluminescence sensor. Biosens Bioelectron 1995;10:501–7. doi:10.1016/0956-5663(95)96925-O.PubMedCrossRefGoogle Scholar
  31. 31.
    Puren AJ, Fantuzzi G, Gu Y, Su MS, Dinarello CA. Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. J Clin Invest 1998;101:711–21. doi:10.1172/JCI1379.PubMedCrossRefGoogle Scholar
  32. 32.
    Stone JH, Hoffman GS, Merkel PA, Min YI, Uhlfelder ML, Hellmann DB, et al. A disease-specific activity index for Wegener’s granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum 2001;44:912–20. doi:10.1002/1529-0131(200104)44:4<912::AID-ANR148>3.0.CO;2-5.PubMedCrossRefGoogle Scholar
  33. 33.
    Khan AM, Elahi F, Hashmi SR, Mahida KH, Ingrams DR. Wegener’s granulomatosis: a rare, chronic and multisystem disease. Surgeon 2006;4:45–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Lamprecht P, Kumanovics G, Mueller A, Csernok E, Komocsi A, Trabandt A, et al. Elevated monocytic IL-12 and TNF-alpha production in Wegener’s granulomatosis is normalized by cyclophosphamide and corticosteroid therapy. Clin Exp Immunol 2002;128:181–6. doi:10.1046/j.1365-2249.2002.01801.x.PubMedCrossRefGoogle Scholar
  35. 35.
    Jonasdottir O, Petersen J, Bendtzen K. Tumour necrosis factor-alpha (TNF), lymphotoxin and TNF receptor levels in serum from patients with Wegener’s granulomatosis. APMIS 2001;109:781–6. doi:10.1034/j.1600-0463.2001.d01-146.x.PubMedCrossRefGoogle Scholar
  36. 36.
    Hewins P, Morgan MD, Holden N, Neil D, Williams JM, Savage CO, et al. IL-18 is upregulated in the kidney and primes neutrophil responsiveness in ANCA-associated vasculitis. Kidney Int 2006;69:605–15. doi:10.1038/ Scholar
  37. 37.
    Hultgren O, Andersson B, Hahn-Zoric M, Almroth G. Serum concentration of interleukin-18 is up-regulated in patients with ANCA-associated vasculitis. Autoimmunity 2007;40:529–31. doi:10.1080/08916930701622783.PubMedCrossRefGoogle Scholar
  38. 38.
    Plater-Zyberk C, Joosten LA, Helsen MM, Sattonnet-Roche P, Siegfried C, Alouani S, et al. Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis. J Clin Invest 2001;108:1825–32.PubMedGoogle Scholar
  39. 39.
    Tissi L, McRae B, Ghayur T, von Hunolstein C, Orefici G, Bistoni F, et al. Role of interleukin-18 in experimental group B streptococcal arthritis. Arthritis Rheum 2004;50:2005–13. doi:10.1002/art.20014.PubMedCrossRefGoogle Scholar
  40. 40.
    Jander S, Stoll G. Increased serum levels of the interferon-gamma-inducing cytokine interleukin-18 in myasthenia gravis. Neurology 2002;59:287–9.PubMedGoogle Scholar
  41. 41.
    Lettesjo H, Hansson T, Bergqvist A, Gronlund J, Dannaeus A. Enhanced interleukin-18 levels in the peripheral blood of children with coeliac disease. Clin Exp Immunol 2005;139:138–43. doi:10.1111/j.1365-2249.2005.02661.x.PubMedCrossRefGoogle Scholar
  42. 42.
    Kim SH, Han SY, Azam T, Yoon DY, Dinarello CA. Interleukin-32: a cytokine and inducer of TNF alpha. Immunity 2005;22:131–42.PubMedGoogle Scholar
  43. 43.
    Dinarello CA, Kim SH. IL-32, a novel cytokine with a possible role in disease. Ann Rheum Dis 2006;65(Suppl 3):iii61–4. doi:10.1136/ard.2006.058511.PubMedCrossRefGoogle Scholar
  44. 44.
    Novick D, Rubinstein M, Azam T, Rabinkov A, Dinarello CA, Kim SH. Proteinase 3 is an IL-32 binding protein. Proc Natl Acad Sci U S A 2006;103:3316–21. doi:10.1073/pnas.0511206103.PubMedCrossRefGoogle Scholar
  45. 45.
    Lamprecht P, Till A, Steinmann J, Aries PM, Gross WL. Current state of biologicals in the management of systemic vasculitis. Ann N Y Acad Sci 2007;1110:261–70. doi:10.1196/annals.1423.028.PubMedCrossRefGoogle Scholar
  46. 46.
    Shoda H, Fujio K, Yamaguchi Y, Okamoto A, Sawada T, Kochi Y, et al. Interactions between IL-32 and tumor necrosis factor alpha contribute to the exacerbation of immune-inflammatory diseases. Arthritis Res Ther 2006;8:R166. doi:10.1186/ar2074.PubMedCrossRefGoogle Scholar
  47. 47.
    Netea MG, Azam T, Ferwerda G, Girardin SE, Walsh M, Park JS, et al. IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism. Proc Natl Acad Sci U S A 2005;102:16309–14. doi:10.1073/pnas.0508237102.PubMedCrossRefGoogle Scholar
  48. 48.
    Paulukat J, Bosmann M, Nold M, Garkisch S, Kampfer H, Frank S, et al. Expression and release of IL-18 binding protein in response to IFN-gamma. J Immunol 2001;167:7038–43.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Molecular GeneticsThe Weizmann Institute of ScienceRehovotIsrael
  2. 2.Department of Medicine BKaplan Medical Center RehovotRehovotIsrael
  3. 3.Division of Infectious DiseasesUniversity of ColoradoDenverUSA
  4. 4.Department of Medicine B Allergy and Clinical ImmunologyKaplan Medical Center RehovotRehovotIsrael

Personalised recommendations