Inhibitor of IkappaB kinase activity, BAY 11-7082, interferes with interferon regulatory factor 7 nuclear translocation and type I interferon production by plasmacytoid dendritic cells.
BACKGROUND
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 IkappaB 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-alpha 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-alpha 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-alpha production in human pDCs. BAY11, although showing the ability to also interfere with tumor necrosis factor (TNF)-alpha production, more strongly inhibited IFN-alpha production than TNF-alpha production by pDCs, in response to TLR ligands. We also found that BAY11 inhibited both in vitro IFN-alpha production by human PBMCs induced by the SLE serum and the in vivo serum IFN-alpha 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.
Miyamoto
Rie
R
First Department of Internal Medicine, Kansai Medical University, 10-15, Fumizono, Moriguchi, Osaka, 570-8506, Japan.
Ito
Tomoki
T
Nomura
Shosaku
S
Amakawa
Ryuichi
R
Amuro
Hideki
H
Katashiba
Yuichi
Y
Ogata
Makoto
M
Murakami
Naoko
N
Shimamoto
Keiko
K
Yamazaki
Chihiro
C
Hoshino
Katsuaki
K
Kaisho
Tsuneyasu
T
Fukuhara
Shirou
S
D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009570:Nitriles / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016898:Interferon-alpha; D009570:Nitriles; D013450:Sulfones; D051550:I-kappa B Kinase
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