title: IL-18 receptors, their role in ligand binding and function: anti-IL-1RAcPL antibody, a potent antagonist of IL-18.
abstract: 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.
authors.affiliation: DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304-1104, USA.
authors.forename: R
authors.initials: R
authors.lastname: Debets
authors.forename: J C
authors.initials: JC
authors.lastname: Timans
authors.forename: T
authors.initials: T
authors.lastname: Churakowa
authors.forename: S
authors.initials: S
authors.lastname: Zurawski
authors.forename: R
authors.initials: R
authors.lastname: de Waal Malefyt
authors.forename: K W
authors.initials: KW
authors.lastname: Moore
authors.forename: J S
authors.initials: JS
authors.lastname: Abrams
authors.forename: A
authors.initials: A
authors.lastname: O'Garra
authors.forename: J F
authors.initials: JF
authors.lastname: Bazan
authors.forename: R A
authors.initials: RA
authors.lastname: Kastelein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D001666:Binding Sites, Antibody; D002460:Cell Line; D002999:Clone Cells; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053577:Interleukin-1 Receptor Accessory Protein; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit; D019169:Jurkat Cells; D008024:Ligands; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011506:Proteins / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000276:immunology*; D053724:Receptors, Interleukin-18; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; C508572:IL18R1 protein, human; C507765:IL1RAP protein, human; C508573:Il18r1 protein, mouse; C507767:Il1rap protein, mouse; D053577:Interleukin-1 Receptor Accessory Protein; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D008024:Ligands; D016328:NF-kappa B; D011506:Proteins; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; D007371:Interferon-gamma