IL-18-Binding Protein Protects Against Lipopolysaccharide- Induced Lethality and Prevents the Development of Fas/Fas Ligand-Mediated Models of Liver Disease in Mice

• Published in: The Journal of immunology (1950) Vol. 167; no. 10; pp. 5913 - 5920
• Main Authors: Faggioni, Raffaella, Cattley, Russell C, Guo, Jane, Flores, Silvia, Brown, Heather, Qi, Meiying, Yin, Songmei, Hill, David, Scully, Sheila, Chen, Ching, Brankow, David, Lewis, Jeffrey, Baikalov, Claudia, Yamane, Harvey, Meng, Tina, Martin, Frank, Hu, Sylvia, Boone, Tom, Senaldi, Giorgio
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-11-2001
• Subjects: Animals; Antibodies - pharmacology; Fas antigen; Fas Ligand Protein; fas Receptor - immunology; fas Receptor - physiology; FasL protein; Female; Glycoproteins - genetics; Glycoproteins - physiology; Granuloma - microbiology; Granuloma - prevention & control; Hepatitis, Animal - chemically induced; Hepatitis, Animal - pathology; Hepatitis, Animal - prevention & control; Humans; Immunoglobulin Fc Fragments - genetics; Intercellular Signaling Peptides and Proteins; Interferon-gamma - biosynthesis; interleukin 18-binding protein; Interleukin-18 - antagonists & inhibitors; Interleukin-18 - metabolism; Lipopolysaccharides; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Propionibacterium acnes - physiology; Recombinant Fusion Proteins - therapeutic use; RNA, Messenger - biosynthesis; Survival Analysis; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.10.5913

IL-18-binding protein (IL-18BP) is a natural IL-18 inhibitor. Human IL-18BP isoform a was produced as fusion construct with human IgG1 Fc and assessed for binding and neutralizing IL-18. IL-18BP-Fc binds human, mouse, and rat IL-18 with high affinity (K(D) 0.3-5 nM) in a BIAcore-based assay. In vitro, IL-18BP-Fc blocks IL-18 (100 ng/ml)-induced IFN-gamma production by KG1 cells (EC(50) = 0.3 microg/ml). In mice challenged with an LD(90) of LPS (15 mg/kg), IL-18BP-Fc (5 mg/kg) administered 10 min before LPS blocks IFN-gamma production and protects against lethality. IL-18BP-Fc administered 10 min before LPS blocks IFN-gamma production induced by LPS (5 mg/kg) with ED(50) of 0.005 mg/kg. Furthermore, IL-18BP-Fc (5 mg/kg) abrogates LPS (5 mg/kg)-induced IFN-gamma production even when administered 6 days before LPS but shows no effect when administered 9 or 12 days before LPS. Given 10 min before LPS challenge to mice primed 12 days in advance with heat-killed Propionibacterium acnes, IL-18BP-Fc prevents LPS-induced liver damage and IFN-gamma and Fas ligand expression. Given at the moment of priming with P. acnes, IL-18BP-Fc decreases P. acnes-induced granuloma formation, macrophage-inflammatory protein-1alpha and macrophage-inflammatory protein-2 production and prevents sensitization to LPS. IL-18BP-Fc also prevents Con A-induced liver damage and IFN-gamma and Fas ligand expression as well as liver damage induced by Pseudomonas aeruginosa exotoxin A or by anti-Fas agonistic Ab. In conclusion, IL-18BP can be engineered and produced in recombinant form to generate an IL-18 inhibitor, IL-18BP-Fc, endowed with remarkable in vitro and in vivo properties of binding and neutralizing IL-18.