Abstract
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-1β 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-1α, 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-1β cluster and therefore should not be included in the IL-1 ligand ancestral family. IL-1α formed from the duplication of IL-1β, and moonlighting functions of pro-IL-1α acted as divergent selection pressures for the observed sequence dissimilarity.
Highlights
The interleukin-1 (IL-1) receptor and ligand families are components of the immune system
There is strong sequence and chromosomal anatomy evidence that IL-1R1, IL-1R2, IL1RAP, IL-1RL1 (ST2), IL-18R1, IL-1RL2 and IL-18RAP are members of the same family formed from ancestral gene duplications of a common proto-IL-1R (Supplementary Data 1, Fig. 1b)
The close proximity to the MAP4K4 gene of this IL-1R1 sub-family and the presence of a duplicate MAP4K4 gene beside the IL-1RAPL2 gene in the reptile and cartilaginous fish clades suggest that IL-1RAPL2 formed from a duplication and
Summary
The interleukin-1 (IL-1) receptor and ligand families are components of the immune system. Nine IL-1 ligand family members occur in a single cluster on human chromosome two and likely formed through a series of gene duplications of the prototypical IL-1 family cytokine IL-1β2,15–17 In this way, IL-1β, IL-1α, IL-36α, IL-36β, IL36γ, IL-36RA, IL-37, IL-38, and IL-1RA are accurately described as family members with shared common ancestry[17,18,19,20,21,22,23]. IL-18 and IL-33, are present on different chromosomes and have low sequence identity, indicating weak evidence for evolutionary relatedness, i.e., homology to IL-1β They have been included into the IL-1 family based largely on structural similarities, the presence of a 12 beta- sheet trefoil fold, as well as overlap in function and the receptors involved[8,24,25,26,27,28]. IL-1β and IL-1α both signal through the type 1 IL-1 receptor (IL-1R1)[2,29], and are both produced as precursors (pro-forms) in cells of the innate immune system in response to an inflammatory stimulus such as a pathogen-associated molecular pattern (PAMP, e.g., LPS), or a damage-associated molecular pattern (DAMP, e.g., HMGB1)[2]
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