IL-18-binding protein protects against lipopolysaccharide-induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice
R. Faggioni et al., IL-18-binding protein protects against lipopolysaccharide-induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice, J IMMUNOL, 167(10), 2001, pp. 5913-5920
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 c
ells (EC50 = 0.3 mug/ml). In mice challenged with an LD90 of LPS (15 mg/kg)
, IL-18BP-Fc (5 mg/kg) administered 10 min before LPS blocks IFN-gamma prod
uction and protects against lethality. IL-18BP-Fc administered 10 min befor
e LPS blocks IFN-gamma production induced by LPS (5 mg/kg) with ED50 of 0.0
05 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 Propionibacter
ium acnes, IL-18BP-Fc prevents LPS-induced liver damage and IFN-gamma and F
as ligand expression. Given at the moment of priming with P. acnes, IL-18BP
-Fc decreases P. acnes-induced granuloma formation, macrophage-inflammatory
protein-1 alpha and macrophage-inflammatory protein-2 production and preve
nts sensitization to LPS. EL-18BP-Fc also prevents Con A-induced liver dama
ge 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 conclu
sion, IL-18BP can be engineered and produced in recombinant form to generat
e an IL-18 inhibitor, IL-18BP-Fc, endowed with remarkabIe in vitro and in v
ivo properties of binding and neutralizing IL-18.