Interleukin-18 (IL-18), a cytokine formerly known as interferon-gamma- (IFN-gamma-) inducing factor, has pleiotropic immunoregulatory functions, including augmentation of IFN-gamma 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 beta-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 alpha (IL-18Ralpha), 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 beta (IL-18Rbeta) 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.

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The results shown here suggest the presence of abnormalities in the IL-12 and/or IL-18 signalling pathways, such as genetic defects in the atopic patients.

A BSTRACTAtopic disorders, such as asthma, eczema and rhinitis, develop due to the interactions between genetic and environmental factors. Atopy is characterized by enhanced IgE responses to environmental antigens. The production of IgE is upregulated by Th2 cytokines, in particular interleukin (IL)-4, and downregulated by Th1 cytokines, in particular interferon (IFN)-γ . In the present review, we present the genetic factors responsible for IgE production and genetic defects in the downregulation (brake) of IgE production, especially in terms of IL-12 and IL-18 signaling, mutations of the IL-12 receptor β 2 chain gene and mutations of the IL-18 receptor α chain gene in atopy. Moreover, we newly present a genetic classification of atopy. There are four categories of genes that control the expression of allergic disorders, which include: (i) antigen recognition; (ii) IgE production (downregulation = brake; and upregulation); (iii) the production and release of mediators; and (iv) events on target organs. In the near future, this genetic classification will facilitate the development of tailor-made treatment.

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