Biological functions of Interleukin - 26

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Project Summary/Abstract: In this proposal, we will define the functions of an understudied cytokine interleukin-26 (IL-26) at the mucosal barrier using human and zebrafish models. Cytokines have pleiotropic functions for both the adaptive and innate arms of the immune system to promote antimicrobial immunity, regulate inflammation, and maintain tissue homeostasis. IL-26, produced by Th17 cells, is associated with inflammatory diseases in humans, such as rheumatoid arthritis, ulcerative colitis, and psoriasis. The underlying role of IL-26 in these inflammatory diseases is not well understood. Since mice do not encode the IL26 gene, studies that address the biology of IL-26 have been lacking. Our understanding of IL-26 biology is primarily restricted to the effect IL-26 has on epithelial cells, due to apparent tissue and cellular restriction of the IL-26 receptor. Moreover, as IL-26 is absent in mice and other rodents, it has posed a significant barrier in understanding its biological functions. As such, studies of IL-26 biology have been limited to in vitro cell culture models. However, we have identified a homolog of human IL-26 in zebrafish that is characterized by a highly conserved IL-10 family signature motif and has similar synteny as in humans. There is extensive sequence and functional conservation between human and zebrafish genomes, including genes involved in innate and adaptive immunity. To this end, we will (i) define the transcription and signaling networks induced by IL-26 in human keratinocytes and (ii) define the role of IL-26 in antimicrobial responses at mucosal surfaces in zebrafish. The proposed experiments will provide unprecedented insight into the biological function of IL-26 in inflammation and antimicrobial immunity, with important implications for the role of IL-26 in initiation and progression of inflammatory disease.