Abstract
Interleukin-17 (IL-17 or IL-17A) production is a hallmark of TH17 cells, a new unique lineage of CD4+ T lymphocytes contributing to the pathogenesis of multiple autoimmune and inflammatory diseases. IL-17 receptor (IL-17R or IL-17RA) is essential for IL-17 biological activity. Emerging data suggest that the formation of a heteromeric and/or homomeric receptor complex is required for IL-17 signaling. Here we show that the orphan receptor IL-17RD (Sef, similar expression to FGF genes or IL-17RLM) is associated and colocalized with IL-17R. Importantly, IL-17RD mediates IL-17 signaling, as evaluated using a luciferase reporter driven by the native promoter of 24p3, an IL-17 target gene. In addition, an IL-17RD mutant lacking the intracellular domain dominant-negatively suppresses IL-17R-mediated IL-17 signaling. Moreover, IL-17RD as well as IL-17R is associated with TRAF6, an IL-17R downstream molecule. These results indicate that IL-17RD is a part of the IL-17 receptor signaling complex, therefore providing novel evidence for IL-17 signaling through a heteromeric and/or homomeric receptor complex.
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Acknowledgements
We thank Dr Xin-Yuan Fu (Indiana University, Indianapolis, USA) for his strong support and suggestions on this project. We are grateful to Drs Reinhard Ebner (Human Genome Science, Inc., Rockville, MD) and Hiroyasu Nakano (Juntendo University, Tokyo, Japan) for providing constructs. This work was supported by a Tsinghua-Yu-Yuan Medical Sciences Fund and grants from the National Natural Science Foundation of China (No. 30530420, 30470888 and 30518002), Chinese National Support Project (2006CB910102) and 973 Project (2002CB513007) to Zhijie Chang, and a China-Canada Joint Health Research Initiative grant to Jim Hu (#CCI-82411) and Zhijie Chang (#30611120522). We thank Dr David M Irwin (University of Toronto, Toronto, Canada) for reading the paper.
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Rong, Z., Wang, A., Li, Z. et al. IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling. Cell Res 19, 208–215 (2009). https://doi.org/10.1038/cr.2008.320
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DOI: https://doi.org/10.1038/cr.2008.320
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