IL-17-Induced Regulation of C/EBPbeta

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DESCRIPTION (provided by applicant): IL-17 is a pro-inflammatory cytokine that is the signature of the newly described "Th17" CD4+ T helper population. Th17 cells and IL-17 play essential host-defensive roles in immunity to extracellular pathogens. Many recent studies by our group and others demonstrated that IL-17 plays a particularly important role in controlling mucocutaneous fungal infections caused by the commensal yeast, Candida albicans. Indeed, humans or mice with IL-17 receptor deficiencies or with antibodies against IL-17 are highly prone to oral and mucocutaneous candidiasis. However, the specific signaling pathways used by IL-17 and its receptor to accomplish immunity to fungi are largely unknown. We have shown that IL-17 activates the CCAAT enhancer binding protein b (C/EBP?) transcription factor, which is required for activation of a majority of IL-17 target genes. In particular, IL-17 controls the alternative translation of C/EBP?, which impacts its ability to regulate downstream gene expression and therefore shape immune responses. In bacterial infections, alternative translation of C/EBP? is required for effective immunity and many of the genes that are affected are IL-17 target genes. However, the biological role of C/EBP? alternative translation has not been demonstrated for fungal infections and the specific connection to IL-17 is unknown. This proposal investigates two aspects of the IL-17-C/EBP? signaling pathway. Aim 1 will assess molecular mechanisms by which IL-17 regulates alternative translation of C/EBP?. We will determine (i) the role of an upstream open reading frame (uORF) within C/EBP?, and (ii) the role of the PI3K/AKT/mTOR and PKR signaling pathways in IL-17-mediated C/EBP? alternative translation. In Aim 2, we will determine the biological significance of C/EBP? alternative translation in oropharyngeal candidiasis (OPC, thrush), a strongly IL-17-dependent mucosal infection caused by Candida albicans. To this end, we will take advantage of a knockin mouse that cannot generate the most common ("LAP") isoform of C/EBP?. The functional consequences of LAP deficiency will be investigated using this model of oral candidiasis. Collectively, these studies will help determine how IL-17 regulates C/EBP? in vitro and the downstream impact in vivo. Understanding the mechanism by which IL-17 mediates signaling, particularly in the context of infection, may aid in the development of drugs, vaccines or treatments in diseases affected by IL-17. PUBLIC HEALTH RELEVANCE: Understanding the role of IL-17 in regulating immunity to infection and its potential pathological contribution in autoimmunity is important for rational dru design. However, the fundamental mechanism by which IL-17 regulates these processes is poorly understood. This proposed research will study the effects of IL-17 on mediating the alternative translation of the transcription factor C/EBP?, an event that is known to modulate IL- 17-mediated signaling.