A single amino acid difference between human and monkey interleukin (IL)-1β dictates effective binding to soluble type II IL-1 receptor

Abstract

Soluble type II interleukin (IL)-1 receptor (sIL1R-II) human IL-1Β with high affinity and neutralizes its activity. Recombinant sILIR-II is considered a potentially useful anti-IL-1 therapeutic, and preclinical studies have been undertaken with this molecule in primates. To better understand the cytokine-receptor interactions occurring in this nonhuman context, monkey IL-1 and IL1R-II were cloned, and their binding abilities were examined in vitro. IL-1Β from cynomolgus monkey was capable of binding and activating the human type I IL-1 receptor. However, unlike human IL-1Β, it was unable to effectively bind and become neutralized by sIL1R-II. Human and cynomolgus IL-1Β proteins are 96% identical, differing by only six amino acids. Structural and mutational analysis revealed that the unique sIL1R-II binding ability of human IL-1Β is due to a single amino acid difference compared with monkey IL-1Β.