The structure and binding mode of interleukin-18

Interleukin-18 (IL-18), a cytokine formerly known as interferon-γ (IFN-γ-) inducing factor, has pleiotropic immunoregulatory functions, including augmentation of IFN-γ, production, Fas-mediated cytotoxicity and developmental regulation of T-lymphocyte helper type I. We determined the solution structure of IL-18 as a first step toward understanding its receptor activation mechanism. It folds into a β-trefoil structure that resembles that of IL-1. Extensive mutagenesis revealed the presence of three sites that are important for receptor activation: two serve as binding sites for IL-18 receptor α (IL-18Rα), located at positions similar to those of IL-1 for IL-1 receptor type I (IL-1RI), whereas the third site may be involved in IL-18 receptor β (IL-18Rβ) binding. The structure and mutagenesis data provide a basis for understanding the IL-18-induced heterodimerization of receptor subunits, which is necessary for receptor activation.