IL-18 receptor beta-induced changes in the presentation of IL-18 binding sites affect ligand binding and signal transduction.
IL-18 is a pleiotropic proinflammatory cytokine that is involved in induction of inflammatory mediators, regulation of the cytotoxic activity of NK cells and T cells, and differentiation and activation of both Th1 and Th2 cells. IL-18 signals through its specific cell surface receptor IL-18R, which comprises two subunits: IL-18R alpha and IL-18R beta. IL-18R alpha alone has a weak affinity for IL-18 binding, while the IL-18R alpha/beta complex has a high affinity. By using several anti-IL-18 mAbs and IL-18 binding protein, we have examined whether these site-specific inhibitors could block the binding of IL-18 to IL-18R alpha and to the IL-18R alpha/beta complex. Here we show that IL-18 binding to IL-18R alpha was inhibited by a neutralizing mAb, 125-2H, while binding of IL-18 to the alpha/beta receptor complex was not. This suggests that IL-18R beta-induced conformational changes may occur in IL-18R alpha upon dimerization, leading to changes in the presentation of IL-18 binding sites. Epitope mapping of 125-2H using human-mouse IL-18 chimeras identified a region in IL-18 that was required for 125-2H recognition. This region, as examined by IL-18R binding and functional analysis, appeared to be critical for triggering signal transduction through the heterodimeric receptor.
Wu
Chengbin
C
Abbott Bioresearch Center, Worcester, MA 01605, USA. chengbin.wu@abbott.com
Sakorafas
Paul
P
Miller
Renee
R
McCarthy
Donna
D
Scesney
Susanne
S
Dixon
Richard
R
Ghayur
Tariq
T
D000818:Animals; D019138:Antibodies, Blocking / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017951:Antigen Presentation / Q000235:genetics; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics; D019281:Dimerization; D018604:Epitope Mapping; D006801:Humans; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit; D008024:Ligands; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D053724:Receptors, Interleukin-18; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; C508572:IL18R1 protein, human; C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D008024:Ligands; D010446:Peptide Fragments; D021122:Protein Subunits; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D011993:Recombinant Fusion Proteins