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Interleukin-18 (IL-18), a cytokine formerly known as interferon-?- (IFN-?-) inducing factor, has pleiotropic immunoregulatory functions, including augmentation of IFN-? 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 ß-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 a (IL-18Ra), 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 ß (IL-18Rß) 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. [ABSTRACT FROM AUTHOR]

Atopic 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 β2 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. [ABSTRACT FROM AUTHOR]

Human interleukin-18 (hIL-18), originally known as an IFN-γ-inducing factor, is a recently cloned cytokine that is secreted by Kupffer cells of the liver and by stimulated macrophages. We have previously established a method of expression and purification of IL-18. The yield however remains low and the insufficient expression of a heterologous protein could be due to skewed codon usage between the expression host and the cDNA donor. The sequence of mature hIL-18 has 37 a.a. rare codons for Escherichia coli in a total of 157 a.a. To overcome this problem, gene synthesis was performed with optimized codons for the expression host E. coli. The final yield of the hIL-18 protein with optimized codons was about five times higher than the yield with the native sequence. Using a minimal medium, this system produces large quantities of labeled proteins that can be used in NMR analysis. Our simple and efficient production system can be applied to the production of other cytokines for new structural and therapeutic use. [Copyright &y& Elsevier]