IL-18 Receptors, Their Role in Ligand Binding and Function: Anti-IL-1RAcPL Antibody, a Potent Antagonist of IL-18

• Published in: The Journal of immunology (1950) 2000-11, Vol.165 (9), p.4950-4956
• Main Authors: Debets, Reno, Timans, Jackie C, Churakowa, Tatyana, Zurawski, Sandra, de Waal Malefyt, Rene, Moore, Kevin W, Abrams, John S, O'Garra, Anne, Bazan, J. Fernando, Kastelein, Robert A
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Binding Sites, Antibody; Cell Line; Clone Cells; Humans; IL-1RAcPL protein; IL-1Rrp1 protein; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; Interleukin 18 receptors; Interleukin-1 Receptor Accessory Protein; Interleukin-18 - antagonists & inhibitors; Interleukin-18 - metabolism; Interleukin-18 Receptor alpha Subunit; Jurkat Cells; Ligands; Mice; NF-kappa B - metabolism; Protein Binding - immunology; Proteins - immunology; Receptors, Interleukin - genetics; Receptors, Interleukin - metabolism; Receptors, Interleukin - physiology; Receptors, Interleukin-1 - immunology; Receptors, Interleukin-18; Th1 Cells - immunology; Th1 Cells - metabolism; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.9.4950

IL-18 is critical in eliciting IFN-gamma production from Th1 cells both in vitro and in vivo. Th1 cells have been implicated in the pathogenesis of autoimmune disorders, making antagonists of IL-18 promising therapeutics. However, specificity and binding characteristics of IL-18R components have only been superficially explored. In this study, we show that IL-1R related protein 1 (IL-1Rrp1) and IL-1R accessory protein-like (IL-1RAcPL) confer responsiveness to IL-18 in a highly specific (no response to other IL-1 ligands) and unique manner (no functional pairing with other IL-1Rs and IL-1R-like molecules). Cotransfection with both receptor components resulted in expression of both low and high affinity binding sites for IL-18 (K:(d) of 11 and 0.4 nM, respectively). We prepared anti-IL-1RAcPL mAb TC30-28E3, which, in contrast to soluble R proteins, effectively inhibited the IL-18-induced activation of NF-kappaB. Quantitative PCR showed that Th1 but not Th2 cells are unique in that they coexpress IL-1Rrp1 and IL-1RAcPL. mAb TC30-28E3 inhibited IL-18-induced production of IFN-gamma by Th1 cells, being at least 10-fold more potent than anti-IL-18 ligand mAb. This study shows that IL-1RAcPL is highly specific to IL-18, is required for high affinity binding of IL-18, and that the anti-IL-1RAcPL mAb TC30-28E3 potently antagonizes IL-18 responses in vitro, providing a rationale for the use of anti-IL-1RAcPL Abs to inhibit Th1-mediated inflammatory pathologies.