Redefining the ancestral origins of the interleukin-1 superfamily

The interleukin-1 (IL-1) receptor and ligand families are components of the immune system. Knowledge of their evolutionary history is essential to understand their function. Using chromosomal anatomy and sequence similarity, we show that IL-1 receptor family members are related and nine members are likely formed from duplication and modification of a proto-IL-1R1 receptor. The IL-1 ligands have a different evolutionary history. The first proto-IL-1 beta gene coincided with proto-IL-1R1 and duplication events resulted in the majority of IL-1 ligand family members. However, large evolutionary distances are observed for IL-1 alpha, IL-18 and IL-33 proteins. Further analysis show that IL-33 and IL-18 have poor sequence similarity and no chromosomal evidence of common ancestry with the IL-1 beta cluster and therefore should not be included in the IL-1 ligand ancestral family. IL-1 alpha formed from the duplication of IL-1 beta, and moonlighting functions of pro-IL-1 alpha acted as divergent selection pressures for the observed sequence dissimilarity.