SARAH GAFFEN

..This review will focus on interleukin (IL)-17, the founding member of the newest subclass of cytokines, which has received considerable attention in the last several years due to its central role in the Th17 system...

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..This article discusses the history of the discovery of Th17 cells, the potential mechanisms of action of IL-17 in autoimmunity, and perspectives for IL-17-targeted cytokine therapy...

..Although immunity to Candida albicans was long considered to be mediated by Th1 cells, new data in both rodent models and in humans have revealed an essential role for the Th17 lineage, and in particular its signature cytokine IL-17...

..Moreover, with the advent of anti-cytokine biologic drugs that target the Th1 and Th17 pathways in autoimmunity, the potential consequences to periodontal disease susceptibility in humans need to be understood...

..In addition, IL-17 synergizes potently with other cytokines, placing it in the center of the inflammatory network. Strikingly, IL-17 has been associated with several bone pathologies, most notably rheumatoid arthritis...

..This study provides a profile of genes regulated by IL-17 and TNF-alpha in osteoblasts and suggests that in bone, the major function of IL-17 is to cooperate and/or synergize with other cytokines to amplify inflammation...

..However, in the last year important new insights into the composition and dynamics of the receptor complex and mechanisms of downstream signal transduction have been made, which will be reviewed here...

..IL-17 sits at the center of many complex diseases that integrate innate and adaptive immune mechanisms and requires careful study to maximize host protective effects and minimize host deleterious effects...

..Therapeutics that antagonize inflammatory cytokines ameliorate inflammation and bone loss and may have broader implications for individuals with systemic diseases in which inflammation and autoimmunity predominate...

..This review will examine what is known regarding IL-17RC function and provide a framework for future work on this subunit and its impact on human health...

..This chapter describes the major molecular properties, biological activities, and known signaling pathways of the IL-17 family, with an emphasis on IL-17A and IL-17RA...

..However, emerging data indicate that the newly-defined Th17 compartment appears to play the predominant role in mucosal candidiasis...

..Here, we summarize the major IL-17 target genes that mediate this cytokine's activities in both autoimmune and chronic diseases as well as during various types of infections...

..Accordingly, these data show that IL-17A negatively regulates adipogenesis and subsequent leptin expression, which correlates with increased bone destruction during OVX...

..Insight into the mechanisms by which IL-17RC signals helps shed light on IL-17-dependent inflammatory responses and may ultimately provide an avenue for therapeutic intervention in IL-17-mediated diseases...

..This study is the first demonstration of LIX expression in bone cells and has implications for inflammatory bone diseases such as arthritis and periodontal disease...

..Together, these findings illustrate a biological function for IL-17A in regulating IL-12-Th1 cell immunity and host responses to an intracellular pathogen...

..These studies provide new insight into the structure-function relationships of IL-17RA and reveal distinct signaling differences among IL-17R family members...

..Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors...

..Together, these data show that NFAT is the crucial sensor of TCR signaling in the IL-17 promoter...

..Strikingly, treatment with IL-17A or IL-17F markedly reduced FRET efficiency, suggesting that IL-17RA subunits within the IL-17R complex undergo a conformational change upon ligand binding...

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..Analysis of IL-17 target gene regulation is key for understanding this important host-defense molecule and also contributes to an understanding of upstream signaling mechanisms used by IL-17, either alone or in concert with TNFalpha...

..These results indicate a nonredundant role for IL-17 in mediating host defense via neutrophil mobilization...

..However, the FN1 domain is also required for high affinity interactions with IL-17. Therefore, although the PLAD is located entirely within FN2, effective ligand binding also involves contributions from the linker and FN1...

..Thus, there are intrinsic signaling differences between IL-2 and IL-15 that can be attributed to differences in activation of the PI3K pathway...

..In particular, the T-cell components that contribute to systemic lupus erythematosus pathogenesis are incompletely defined...

..Thus, C/EBP family members, particularly C/EBPdelta, appear to be important for the functional cooperation between IL-17 and TNFalpha...

..Moreover, using that information, we aim to design specific blockers of the IL-17 receptor that might ultimately be used therapeutically to treat autoimmune conditions. ..

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