An ancient evolutionary origin for IL-1 cytokines

Inflammation is widely considered a hallmark of animal immune responses. In mammals, this process is mediated in part by pro-inflammatory cytokines of the interleukin 1 (IL-1) superfamily, which establish and support microenvironments that regulate immune cell activity. However, the evolutionary origins of IL-1 cytokines remain elusive, as homologous proteins have been difficult to confidently identify outside vertebrates using sequence-based approaches. Although IL-1 family members have been described in all vertebrate lineages, including cartilaginous and jawless fishes, their distribution and evolutionary relationships beyond these groups remain unclear. Here we applied protein structure prediction algorithms to identify genes encoding a previously unrecognized family of IL-1 proteins (termed 'IL-1anc' to reflect their ancestral evolutionary origin) with homologues throughout Eumetazoa. Here, using Petromyzon marinus (sea lamprey) and Strongylocentrotus purpuratus (purple sea urchin) as model systems, we demonstrate that IL-1anc proteins share key features with mammalian IL-1α/IL-1β, including expression patterns, subcellular localization and post-translational processing. Together with previous evidence identifying other IL-1 axis components in invertebrates, our data support a model in which the IL-1 superfamily and associated circuitry represent a foundational module of animal immunity that far predates the jawed vertebrates.