IL-18-binding protein protects against lipopolysaccharide- induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice.
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.
Faggioni
R
R
Amgen, Inc., Thousand Oaks, CA 91320, USA. faggioni@amgen.com
Cattley
R C
RC
Guo
J
J
Flores
S
S
Brown
H
H
Qi
M
M
Yin
S
S
Hill
D
D
Scully
S
S
Chen
C
C
Brankow
D
D
Lewis
J
J
Baikalov
C
C
Yamane
H
H
Meng
T
T
Martin
F
F
Hu
S
S
Boone
T
T
Senaldi
G
G
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D053222:Fas Ligand Protein; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006099:Granuloma / Q000382:microbiology / Q000517:prevention & control; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011425:Propionibacterium acnes / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D006023:Glycoproteins; D007141:Immunoglobulin Fc Fragments; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C118370:interleukin-18 binding protein; D007371:Interferon-gamma