Elevated serum levels of free interleukin-18 in adult-onset Still's disease.
OBJECTIVE
IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases.


METHODS
An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients.


RESULTS
Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; P < 0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM.


CONCLUSIONS
Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.
Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland.
Charlotte
C
Girard
Department of Internal Medicine 3, University Erlangen-Nuremberg, Erlangen, Germany.
Jürgen
J
Rech
Lyndin Group, Inc., Baltimore, MD, USA.
Michael
M
Brown
Division of Immunology and Allergy, University Hospitals of Geneva.
Danièle
D
Allali
Division of Immunology and Allergy, University Hospitals of Geneva.|Department of Genetics and Laboratory Medicine, University of Geneva, Geneva.
Pascale
P
Roux-Lombard
Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV).
François
F
Spertini
AB2 Bio, Innovation Park, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Eduardo J
EJ
Schiffrin
Department of Internal Medicine 3, University Erlangen-Nuremberg, Erlangen, Germany.
Georg
G
Schett
Department of Internal Medicine 3, University Erlangen-Nuremberg, Erlangen, Germany.
Bernhard
B
Manger
Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland.|Department of Genetics and Laboratory Medicine, University of Geneva, Geneva.
Sylvette
S
Bas
AB2 Bio, Innovation Park, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Greg
G
Del Val
Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland, cem.gabay@hcuge.ch.
Cem
C
Gabay
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D007964:Leukocytosis / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D016706:Still's Disease, Adult-Onset / Q000097:blood*
D015415:Biomarkers; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein; D002097:C-Reactive Protein; D005293:Ferritins; D000410:Alanine Transaminase
IL-18BP; adult-onset Still’s disease; free IL-18