Interleukin-17 gene regulation in T cells
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IL-17 is the founding member of a novel family of cytokines and plays a central role in inflammation, rheumatoid arthritis and lung disease. However, little is known about how IL-17 expression is controlled. This study explores three aspects of the mechanism of IL-17 gene regulation: proximal cis -acting elements in the human IL-17 promoter that respond to T cell receptor (TCR) signaling, signals provided by antigen presenting cells that are necessary for optimal IL-17 production in mouse primary cells, and IL-17 gene regulation in a mouse cell model. To define cis -acting elements important for IL-17 gene regulation, we cloned 1 kb of a putative promoter, and found that it was active in Jurkat T cells. Studies using pharmacological inhibitors, over-expression systems and Jurkat sublines all indicated a role for the transcription factor nuclear factor of activated T cells (NFAT). We then showed that a region containing two NFAT sites was sufficient for TCR inducible promoter activity. Moreover, mutations of these sites dramatically reduced reporter gene activity. Chromatin immunoprecipitation assays showed occupancy of NFAT at this region in vivo . Together, these data show that NFAT is a crucial sensor of TCR signaling in the IL-17 promoter. IL-17 is primarily made by T cells, but relatively little is known about the requirements and mechanisms for IL-17 expression in mouse lymphocytes. Like many cytokines, we found that IL-17 was induced rapidly in primary lymphocytes after CD3 crosslinking. Although a panel of costimulatory signals failed to increase IL-I7 levels, we found that IL-23, produced by activated dendritic cells, increased IL-17 production both independently and in conjugation with TCR signals. To begin to characterize signaling pathways required for IL-17 production in mice, we identified an IL-17-producing EL4 T cell line. Next, we cloned a 3000 by putative promoter, and showed that it was transcriptionally active in EL4 cells. This cell line will be a useful tool for further work on the mouse IL-17 promoter study in vitro . Overall, these studies are the first report about the mechanism of IL-17 gene regulation, and they may offer new opportunities for therapeutic intervention for diseases involving this cytokine.