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and Characterization of a Functional IL-18 Receptor Complex 1
* University of Colorado Health Sciences Center, Denver, CO 80262;
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel;
Korea Research Institute of Bioscience and Biotechnology, Yuseong Taejon, Republic of Korea; and
Department of Immunology, College of Medicine, KonKuk University, Chungju, Republic of Korea
Steady state mRNA levels in various human tissues reveal that the proinflammatory cytokine IL-18 is constitutively and ubiquitously expressed. However, limited IL-18R 
-chain (IL-18R) expression in tissues may restrict ligand-acting sites and contribute to a specific response for IL-18. To study the IL-18R complex, [125I]IL-18 was studied for binding to the cell surface receptors of IL-18-responsive NK and macrophagic KG-1 cells. After cross-linking, [125I]IL-18 formed three IL-18R complexes with sizes of approximately 93, 160, and 220 kDa. In KG-1 cells, Scatchard analysis revealed the presence of 135 binding sites/cell, with an apparent dissociation constant (Kd) of 250 pM; in NK cells, there were 350 binding sites per cell with an apparent Kd of 146 pM. Each domain of extracellular IL-18R was cloned and individually expressed in Escherichia coli. An mAb specifically recognized the membrane-proximal third domain; this mAb blocked IL-18-induced IFN-
production in NK cells. Furthermore, deletion of the membrane-proximal third domain of IL-18R prevented the formation of IL-18R ternary complex with IL-18R 
-chain. The present studies demonstrate that the biologically active IL-18R complex requires the membrane-proximal third Ig-like domain in IL-18R for the formation of IL-18R ternary complex as well as for signal transduction involved in IL-18-induced IFN- in NK cells.
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