IL1R9 Is Evolutionarily Related to IL18BP and May Function as an IL-18 Receptor

J Immunol. 2017 Jan 1;198(1):270-278. doi: 10.4049/jimmunol.1500648. Epub 2016 Nov 23.


The IL-1 families of ligands and receptors exhibit similarity of coding sequences, protein structures, and chromosomal positions, suggesting that they have arisen via duplication of ancestral genes. Within these families there is selectivity in ligand-receptor interactions as well as promiscuity. IL-18 and its receptor are members of these families. IL-18 is recognized as binding to the protein products of the IL18R1 and IL18RAP genes, and with high affinity to a separate IL-18 binding protein (IL-18BP). However, IL-18BP is anomalous, as it exhibits little resemblance to IL-18R proteins. Additionally, IL-18 is produced in the brain in medial habenula neurons, which project IL-18-containing axons to the interpeduncular nucleus. However, there is a lack of focal IL-18R expression in their terminal field. Given these anomalies, we hypothesized that another receptor for IL-18 may exist, and that IL18BP is evolutionarily related to this receptor. We examined Ensembl and National Center for Biotechnology Information databases to identify available IL18BP records (n = 86 species) and show through bioinformatics approaches that across mammalian species with IL18BP genes, IL-18BP is consistently most similar to IL-1R9 (IL-1R accessory protein-like 2), another member of the IL-1R family. IL-1R9 and the related IL-1R8, but not other IL-1R family members, exhibit an amino acid sequence similar to binding site A of human and viral IL-18BPs. Conserved intron/exon boundaries, protein structure, and key binding site amino acids suggest that IL18BP and IL1R9 are evolutionarily related, and that IL-1R9 and IL-1R8 may bind IL-18.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Computational Biology
  • Evolution, Molecular
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Receptors, Interleukin-1 / genetics*
  • Receptors, Interleukin-18 / genetics*
  • Sequence Homology


  • Intercellular Signaling Peptides and Proteins
  • Receptors, Interleukin-1
  • Receptors, Interleukin-18
  • interleukin-18 binding protein