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

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 onl...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.165.9.4950