Evolutionary Analysis of the Mammalian IL‐17 Cytokine Family Suggests Conserved Roles in Female Fertility

Abstract

ABSTRACTProblemThe interleukin‐17 (IL‐17) family includes pro‐inflammatory cytokines IL‐17A‐F with important roles in mucosal defence, barrier integrity and tissue regeneration. IL‐17A can be dysregulated in fertility complications, including pre‐eclampsia, endometriosis and miscarriage. Because mammalian subclasses (eutherian, metatherian, and prototherian) have different related reproductive strategies, IL‐17 genes and proteins were investigated in the three mammalian classes to explore their involvement in female fertility.Method of StudyGene and protein sequences for IL‐17s are found in eutherian, metatherian and prototherian mammals. Through synteny and multiple sequence protein alignment, the relationships among mammalian IL‐17s were inferred. Publicly available datasets of early pregnancy stages and female fertility in therian mammals were collected and analysed to retrieve information on IL‐17 expression.ResultsSynteny mapping and phylogenetic analyses allowed the classification of mammalian IL‐17 family orthologs of human IL‐17. Despite differences in their primary amino acid sequence, metatherian and prototherian IL‐17s share the same tertiary structure as human IL‐17s, suggesting similar functions. The analysis of available datasets for female fertility in therian mammals shows up‐regulation of IL‐17A and IL‐17D during placentation. IL‐17B and IL‐17D are also found to be over‐expressed in human fertility complication datasets, such as endometriosis or recurrent implantation failure.ConclusionsThe conservation of the IL‐17 gene and protein across mammals suggests similar functions in all the analysed species. Despite significant differences, the upregulation of IL‐17 expression is associated with the establishment of pregnancy in eutherian and metatherian mammals. The dysregulation of IL‐17s in human reproductive disorders suggests them as a potential therapeutic target.