Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease.

OBJECTIVE Interleukin-18 (IL-18) is a proinflammatory cytokine that is involved in immunologically mediated tissue damage, but its bioactivity is regulated in vivo by its soluble decoy receptor, IL-18 binding protein (IL-18BP). This study was undertaken to determine levels of IL-18 and IL-18 binding inhibition in the blood of patients with adult-onset Still's disease (ASD). METHODS Serum concentrations of IL-18 in ASD patients were compared by enzyme-linked immunosorbent assay (ELISA) with those in patients with other systemic rheumatic diseases and healthy controls. The biologically active mature protein of IL-18 was detected by Western blot analysis with anti-IL-18 antibody and its induction of interferon-gamma (IFNgamma) secretion from IL-18-responding human myelomonocytic KG-1 cells. The inhibitory activity on IL-18 binding to its receptor was determined by 125I-IL-18 binding inhibition assay using the Chinese hamster ovary cell line transfected with a murine IL-18 receptor (CHO-K1/mIL-18R). RESULTS Concentrations of serum IL-18 were extremely elevated in patients with active ASD compared with those in patients with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, Sjogren's syndrome, or healthy individuals. Levels of IL-18 were found to correlate with serum ferritin values and disease severity in ASD. Western blot analysis revealed that serum samples from patients with active ASD contained an 18-kd polypeptide of IL-18, corresponding in size to the mature form. Accordingly, the samples were able to induce IFNgamma secretion from KG-1 cells, which was largely abolished by neutralizing anti-IL-18 antibody. However, the level of IL-18 bioactivity was more than 10-fold weaker than the concentration of IL-18 protein measured by ELISA. Serum samples from patients with active ASD showed an inhibitory effect on the binding of 125I-IL-18 to CHO-K1/mIL-18R cells, and this activity was associated with elevation of IL-18. CONCLUSION These data indicate that systemic overproduction of IL-18 may be closely related to the pathogenesis of ASD, despite the restriction on its inflammatory activity by IL-18 binding inhibitors such as IL-18BP. The disease activity appears to be determined on the basis of the relative levels of IL-18 and its specific inhibitors.

[1]  H. Young,et al.  In vivo administration of IL‐18 can induce IgE production through Th2 cytokine induction and up‐regulation of CD40 ligand (CD154) expression on CD4+ T cells , 2000, European journal of immunology.

[2]  I. McInnes,et al.  A proinflammatory role for IL-18 in rheumatoid arthritis. , 1999, The Journal of clinical investigation.

[3]  H. Kolb,et al.  IL-18 inhibits diabetes development in nonobese diabetic mice by counterregulation of Th1-dependent destructive insulitis. , 1999, Journal of immunology.

[4]  K. Kohno,et al.  Oversecretion of IL‐18 in haemophagocytic lymphohistiocytosis: a novel marker of disease activity , 1999, British journal of haematology.

[5]  A. Fusco,et al.  Bioactive IL-18 expression is up-regulated in Crohn's disease. , 1999, Journal of immunology.

[6]  T. Tanimoto,et al.  Cloning and expression of interleukin‐18 binding protein , 1999, FEBS letters.

[7]  C. Moskaluk,et al.  IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. , 1998, Journal of immunology.

[8]  G. Fantuzzi,et al.  Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. , 1999, Immunity.

[9]  T. Born,et al.  Cloning of a Novel Receptor Subunit, AcPL, Required for Interleukin-18 Signaling* , 1998, The Journal of Biological Chemistry.

[10]  M. Su,et al.  Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. , 1998, The Journal of clinical investigation.

[11]  S. Al-Sedairy,et al.  A mixed Th1/Th2 cell cytokine response predominates in systemic onset juvenile rheumatoid arthritis: immunoregulatory IL-10 function. , 1998, Clinical immunology and immunopathology.

[12]  M. Kikuchi,et al.  Elevated serum interleukin 6, interferon-gamma, and tumor necrosis factor-alpha levels in patients with adult Still's disease. , 1998, The Journal of rheumatology.

[13]  T. Tanimoto,et al.  A simple and sensitive bioassay for the detection of human interleukin-18/interferon-gamma-inducing factor using human myelomonocytic KG-1 cells. , 1997, Journal of immunological methods.

[14]  H. Okamura,et al.  IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice. , 1997, Journal of immunology.

[15]  K. Torigoe,et al.  Purification and Characterization of the Human Interleukin-18 Receptor* , 1997, The Journal of Biological Chemistry.

[16]  R. Kastelein,et al.  IGIF Does Not Drive Th1 Development but Synergizes with IL-12 for Interferon-γ Production and Activates IRAK and NFκB , 1997 .

[17]  H. Okamura,et al.  Interleukin-12 (IL-12) and IL-18 synergistically induce the fungicidal activity of murine peritoneal exudate cells against Cryptococcus neoformans through production of gamma interferon by natural killer cells , 1997, Infection and immunity.

[18]  M. Ikeda,et al.  Characterization of anti-human interleukin-18 (IL-18)/interferon-gamma-inducing factor (IGIF) monoclonal antibodies and their application in the measurement of human IL-18 by ELISA. , 1997, Journal of immunological methods.

[19]  H. Kolb,et al.  Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2. , 1997, The Journal of clinical investigation.

[20]  M. Su,et al.  Activation of Interferon-γ Inducing Factor Mediated by Interleukin-1β Converting Enzyme , 1997, Science.

[21]  H. Okamura,et al.  IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones. , 1996, Journal of immunology.

[22]  T. Tanimoto,et al.  Interferon‐γ‐inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin‐12 for interferon‐γ production , 1996 .

[23]  H. Okamura,et al.  Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. , 1996, Journal of immunology.

[24]  M. Gayle,et al.  T1/ST2 Signaling Establishes It as a Member of an Expanding Interleukin-1 Receptor Family (*) , 1996, The Journal of Biological Chemistry.

[25]  S. Dower,et al.  IL-1Rrp Is a Novel Receptor-like Molecule Similar to the Type I Interleukin-1 Receptor and Its Homologues T1/ST2 and IL-1R AcP (*) , 1996, The Journal of Biological Chemistry.

[26]  H. Okamura,et al.  Cloning of a new cytokine that induces IFN-γ production by T cells , 1995, Nature.

[27]  H. Okamura,et al.  A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock , 1995, Infection and immunity.

[28]  A. Martini,et al.  Elevated circulating interleukin-7 levels in patients with systemic juvenile rheumatoid arthritis. , 1995, The Journal of rheumatology.

[29]  P. Liebmann,et al.  Serum cytokines in juvenile rheumatoid arthritis. Correlation with conventional inflammation parameters and clinical subtypes. , 1995, Arthritis and rheumatism.

[30]  M. Kahn,et al.  Serum ferritin and isoferritins are tools for diagnosis of active adult Still's disease. , 1994, The Journal of rheumatology.

[31]  S. Albani,et al.  Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. , 1994, The Journal of clinical investigation.

[32]  D. Isenberg,et al.  Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European Community. , 1993, Arthritis and rheumatism.

[33]  D. Sackett,et al.  Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. , 1992, Arthritis and rheumatism.

[34]  M. Akizuki,et al.  Preliminary criteria for classification of adult Still's disease. , 1992, The Journal of rheumatology.

[35]  K. Weinberg,et al.  Defining protective responses to pathogens: cytokine profiles in leprosy lesions. , 1991, Science.

[36]  A. Martini,et al.  Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. , 1991, Arthritis and rheumatism.

[37]  J. Esdaile,et al.  Adult Still's Disease: Manifestations, Disease Course, and Outcome in 62 Patients , 1991, Medicine.

[38]  J. Dayer,et al.  Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. , 1990, Arthritis and rheumatism.

[39]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[40]  M. Linder,et al.  Translational regulation of ferritin synthesis in rat spleen: effects of iron and inflammation. , 1989, Biochemical and biophysical research communications.

[41]  P. Aisen,et al.  Interactions between isolated hepatocytes and kupffer cells in iron metabolism: A possible role for ferritin as an iron carrier protein , 1988, Hepatology.

[42]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[43]  P. Aisen,et al.  Iron metabolism in the erythrophagocytosing Kupffer cell , 1988, Hepatology.

[44]  A. Ohta,et al.  Adult Still's disease: review of 228 cases from the literature. , 1987, The Journal of rheumatology.

[45]  J. Ferreirós,et al.  Adult onset Still's disease: experience in 23 patients and literature review with emphasis on organ failure. , 1987, Seminars in arthritis and rheumatism.

[46]  S. Eto,et al.  INCREASED SERUM FERRITIN LEVELS IN ADULT STILL'S DISEASE , 1987, The Lancet.

[47]  L. Cooperstein,et al.  Adult-onset Still's disease. Clinical course and outcome. , 1987, Arthritis and rheumatism.

[48]  L. Notarangelo,et al.  Enhanced interleukin 1 and depressed interleukin 2 production in juvenile arthritis. , 1986, The Journal of rheumatology.

[49]  J F Fries,et al.  The 1982 revised criteria for the classification of systemic lupus erythematosus. , 1982, Arthritis and rheumatism.

[50]  A. Masi.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). , 1980, Bulletin on the rheumatic diseases.

[51]  James F. Fries,et al.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. , 1980, Arthritis and rheumatism.

[52]  A. Bohan,et al.  Polymyositis and dermatomyositis (second of two parts). , 1975 .

[53]  O. James,et al.  PAIN IN GASTRIC ULCER , 1974 .

[54]  E. Bywaters.  Still's disease in the adult. , 1971, Annals of the rheumatic diseases.