Revisiting the origin of interleukin 1 in anamniotes and sub-functionalization of interleukin 1 in amniotes.

The cytokine interleukin 1 (IL-1) is an evolutionary innovation of vertebrates. Fish and amphibian have one gene, while mammals have two copies of , and , with distinct expression patterns and differences in their proteolytic activation. Our current understanding of the evolutionary history of IL-1 is mainly based on phylogenetic analysis, but this approach provides no information on potentially different functions of IL-1 homologues, and it remains unclear which biological activities identified for IL-1α and IL-1β in mammals are present in lower vertebrates. Here, we use and experimental models to examine the expression patterns and cleavage of IL-1 proteins from various species. We found that IL-1 in the teleost medaka shares the transcriptional patterns of mammalian IL-1α, and its processing also resembles that of mammalian IL-1α, which is sensitive to cysteine protease inhibitors specific for the calpain and cathepsin families. By contrast, IL-1 proteins in reptiles also include biological properties of IL-1β. Therefore, we propose that the duplication of the ancestral gene led to the segregation of expression patterns and protein processing that characterizes the two extant forms of IL-1 in mammals.