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.
| Original language | English |
|---|---|
| Article number | R87 |
| Journal | Arthritis Research and Therapy |
| Volume | 12 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2010 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Rheumatology
- Immunology
- Immunology and Allergy
- Medicine(all)
Cite this
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. / Miyamoto, Rie; Ito, Tomoki; Nomura, Shosaku; Amakawa, Ryuichi; Amuro, Hideki; Katashiba, Yuichi; Ogata, Makoto; Murakami, Naoko; Shimamoto, Keiko; Yamazaki, Chihiro; Hoshino, Katsuaki; Kaisho, Tsuneyasu; Fukuhara, Shirou.
In: Arthritis Research and Therapy, Vol. 12, No. 3, R87, 2010.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Miyamoto, Rie
AU - Ito, Tomoki
AU - Nomura, Shosaku
AU - Amakawa, Ryuichi
AU - Amuro, Hideki
AU - Katashiba, Yuichi
AU - Ogata, Makoto
AU - Murakami, Naoko
AU - Shimamoto, Keiko
AU - Yamazaki, Chihiro
AU - Hoshino, Katsuaki
AU - Kaisho, Tsuneyasu
AU - Fukuhara, Shirou
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77952054608&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952054608&partnerID=8YFLogxK
U2 - 10.1186/ar3014
DO - 10.1186/ar3014
M3 - Article
C2 - 20470398
AN - SCOPUS:77952054608
VL - 12
JO - Arthritis Research and Therapy
JF - Arthritis Research and Therapy
SN - 1478-6354
IS - 3
M1 - R87
ER -