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Arthritis Res Ther. 2010; 12(3): R87.
Published online May 14, 2010. doi:  10.1186/ar3014
PMCID: PMC2911871
Inhibitor of IκB kinase activity, BAY 11-7082, interferes with interferon regulatory factor 7 nuclear translocation and type I interferon production by plasmacytoid dendritic cells
Rie Miyamoto,1 Tomoki Ito,corresponding author1 Shosaku Nomura,1 Ryuichi Amakawa,1 Hideki Amuro,1 Yuichi Katashiba,1 Makoto Ogata,1 Naoko Murakami,1 Keiko Shimamoto,1 Chihiro Yamazaki,2,3 Katsuaki Hoshino,2 Tsuneyasu Kaisho,2,3,4 and Shirou Fukuhara1
1First Department of Internal Medicine, Kansai Medical University, 10-15, Fumizono, Moriguchi, Osaka, 570-8506, Japan
2Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
3Department of Allergy and Immunology, Osaka University Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
4Department of Supramolecular Biology, Graduate School of Nanobioscience, Yokohama City University, 1-7-29, Suehiro, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
corresponding authorCorresponding author.
Rie Miyamoto: taniokar/at/takii.kmu.ac.jp; Tomoki Ito: itot/at/takii.kmu.ac.jp; Shosaku Nomura: nomurash/at/hirakata.kmu.ac.jp; Ryuichi Amakawa: amakawa/at/takii.kmu.ac.jp; Hideki Amuro: amuroh/at/takii.kmu.ac.jp; Yuichi Katashiba: katashiy/at/takii.kmu.ac.jp; Makoto Ogata: ogatam/at/takii.kmu.ac.jp; Naoko Murakami: murakamn/at/hirakata.kmu.ac.jp; Keiko Shimamoto: shimamok/at/hirakata.kmu.ac.jp; Chihiro Yamazaki: yama-chi/at/rcai.riken.jp; Katsuaki Hoshino: hoshino/at/rcai.riken.jp; Tsuneyasu Kaisho: tkaisho/at/rcai.riken.jp; Shirou Fukuhara: fukuhara/at/takii.kmu.ac.jp
Received February 15, 2010; Revised April 27, 2010; Accepted May 14, 2010.
Abstract
Introduction
Plasmacytoid dendritic cells (pDCs) play not only a central role in the antiviral immune response in innate host defense, but also a pathogenic role in the development of the autoimmune process by their ability to produce robust amounts of type I interferons (IFNs), through sensing nucleic acids by toll-like receptor (TLR) 7 and 9. Thus, control of dysregulated pDC activation and type I IFN production provide an alternative treatment strategy for autoimmune diseases in which type I IFNs are elevated, such as systemic lupus erythematosus (SLE). Here we focused on IκB kinase inhibitor BAY 11-7082 (BAY11) and investigated its immunomodulatory effects in targeting the IFN response on pDCs.
Methods
We isolated human blood pDCs by flow cytometry and examined the function of BAY11 on pDCs in response to TLR ligands, with regards to pDC activation, such as IFN-α production and nuclear translocation of interferon regulatory factor 7 (IRF7) in vitro. Additionally, we cultured healthy peripheral blood mononuclear cells (PBMCs) with serum from SLE patients in the presence or absence of BAY11, and then examined the inhibitory function of BAY11 on SLE serum-induced IFN-α production. We also examined its inhibitory effect in vivo using mice pretreated with BAY11 intraperitonealy, followed by intravenous injection of TLR7 ligand poly U.
Results
Here we identified that BAY11 has the ability to inhibit nuclear translocation of IRF7 and IFN-α production in human pDCs. BAY11, although showing the ability to also interfere with tumor necrosis factor (TNF)-α production, more strongly inhibited IFN-α production than TNF-α production by pDCs, in response to TLR ligands. We also found that BAY11 inhibited both in vitro IFN-α production by human PBMCs induced by the SLE serum and the in vivo serum IFN-α level induced by injecting mice with poly U.
Conclusions
These findings suggest that BAY11 has the therapeutic potential to attenuate the IFN environment by regulating pDC function and provide a novel foundation for the development of an effective immunotherapeutic strategy against autoimmune disorders such as SLE.
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