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, Tomoki Ito, Shosaku Nomura, Ryuichi Amakawa, Hideki Amuro, Yuichi Katashiba, Makoto Ogata, Naoko Murakami, Keiko Shimamoto, Chihiro Yamazaki, Katsuaki Hoshino, Tsuneyasu Kaisho, Shirou Fukuhara

Research output: Contribution to journalArticle

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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 languageEnglish
Article numberR87
JournalArthritis Research and Therapy
Volume12
Issue number3
DOIs
Publication statusPublished - 2010
Externally publishedYes

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Interferon Regulatory Factor-7
Dendritic Cells
Interferons
Phosphotransferases
Systemic Lupus Erythematosus
Interferon Type I
Poly U
Toll-Like Receptors
Ligands
Serum
Blood Cells
Tumor Necrosis Factor-alpha
Toll-Like Receptor 7
Toll-Like Receptor 9
3-(4-methylphenylsulfonyl)-2-propenenitrile
Innate Immunity
Intravenous Injections
Nucleic Acids
Autoimmune Diseases
Antiviral Agents

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 journalArticle

Miyamoto, R, Ito, T, Nomura, S, Amakawa, R, Amuro, H, Katashiba, Y, Ogata, M, Murakami, N, Shimamoto, K, Yamazaki, C, Hoshino, K, Kaisho, T & Fukuhara, S 2010, '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', Arthritis Research and Therapy, vol. 12, no. 3, R87. https://doi.org/10.1186/ar3014
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. / 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. In: Arthritis Research and Therapy. 2010 ; Vol. 12, No. 3.
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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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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.

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