The combination of soluble IL-18Ralpha and IL-18Rbeta chains inhibits IL-18-induced IFN-gamma.
J Interferon Cytokine Res
; 22(5): 593-601, 2002 May.
Article
em En
| MEDLINE
| ID: mdl-12060498
ABSTRACT
Although the beta chain of interleukin-18 receptor (IL-18Rbeta) is required for signaling, the soluble (extracellular) form does not bind IL-18, and its role in inhibiting IL-18 is unclear. In the present study, both the soluble human IL-18 ligand binding alpha chain (sIL-18Ralpha) and the sIL-18Rbeta chain were investigated for inhibition of IL-18-induced interferon-gamma (IFN-gamma) production in human peripheral blood mononuclear cells (PBMC), whole blood, and KG-1 macrophage and natural killer (NK) cell lines. Neutralization of IL-18 by soluble receptors was compared with that of the IL-18 binding protein (IL-18BP). An equimolar concentration IL-18BP inhibited 90% of IL-18 activity, whereas a 4-fold molar excess of sIL-18Ralpha had no effect. A dimeric construct of sIL-18Ralpha linked to the Fc domain of IgG1 (sIL-18RalphaFc) increased IL-18 activity 2.5-fold. In PBMC stimulated with lypopolysaccharide (LPS) or in whole blood stimulated with Staphylococcus epidermidis, 3 nM IL-18BP reduced IFN-gamma by 80%, whereas IL-18RalphaFc had no effect. A construct of the sIL-18Rbeta linked to Fc (sIL-18RbetaFc) did not affect IL-18-induced IFN-gamma even at 80-fold molar excess of IL-18. However, the combination of both soluble receptors reduced IFN-gamma by 80%. In KG-1 cells, a 50% reduction in IL-18 activity was observed using an 80-fold molar excess of sIL-18RalphaFc but only in the presence of sIL-18RbetaFc. Similarly, a 50% reduction was observed using sIL-18RbetaFc in the presence of a molar excess of sIL-18RalphaFc. Similar inhibition was observed in NK cells. These studies reveal that the combination of the ligand-binding and the nonligand-binding extracellular domains of IL-18R is needed to inhibit IL-18, whereas IL-18BP neutralizes at equimolar concentration.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interferon gama
/
Receptores de Interleucina
/
Interleucina-18
Limite:
Adult
/
Humans
Idioma:
En
Revista:
J Interferon Cytokine Res
Ano de publicação:
2002
Tipo de documento:
Article