Abstract
Regulation of antigen-presenting cells (APC) is crucial in controlling allograft rejection. Dendritic cells (DC) are the most potent APC and must mature to present antigens to T-cell receptors. During DC maturation, nuclear factor-κB (NF-κB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-κB proteins and examined its immunoregulatory effects on human monocyte-derived DC (Mo-DC). Regulatory Mo-DC were generated by pretreatment with DHMEQ before LPS stimulation, which were termed dl-DC. DHMEQ pretreatment (5 μg/ml) completely inhibited nuclear translocation of activated NF-κB. DHMEQ significantly inhibited DC production of κproinflammatory cytokines (IL-6, TNF-α, and IL-12 p70) in a dose-dependent manner. IL-12 was most potently inhibited. However, IL-10 production by dl-DC was only moderately affected by DHMEQ. Although CD40 and the expression of HLA-DR (HLA-DR) expression on dl-DC was downregulated, CD80 and CD86 expression was moderately upregulated. Induction of T helper 1 cell responses was efficiently impaired by dl-DC. This confirmed that DHMEQ-treated Mo-DC exhibited immunoregulatory effects. These findings suggest that DHMEQ has potential as an immunosuppressive drug for human immune cells.
| Original language | English |
|---|---|
| Pages (from-to) | 763-770 |
| Number of pages | 8 |
| Journal | Human Immunology |
| Volume | 71 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2010 Aug |
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Keywords
- Dendritic cells
- Immunoregulation
- NF-κB inhibitor
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
Regulation of human dendritic cells by a novel specific nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin. / Shinoda, Kazunobu; Nakagawa, Ken; Kosaka, Takeo; Tanaka, Nobuyuki; Maeda, Takahiro; Kono, Hidaka; Mizuno, Ryuichi; Kikuchi, Eiji; Miyajima, Akira; Umezawa, Kazuo; Oya, Mototsugu.
In: Human Immunology, Vol. 71, No. 8, 08.2010, p. 763-770.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of human dendritic cells by a novel specific nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin
AU - Shinoda, Kazunobu
AU - Nakagawa, Ken
AU - Kosaka, Takeo
AU - Tanaka, Nobuyuki
AU - Maeda, Takahiro
AU - Kono, Hidaka
AU - Mizuno, Ryuichi
AU - Kikuchi, Eiji
AU - Miyajima, Akira
AU - Umezawa, Kazuo
AU - Oya, Mototsugu
PY - 2010/8
Y1 - 2010/8
N2 - Regulation of antigen-presenting cells (APC) is crucial in controlling allograft rejection. Dendritic cells (DC) are the most potent APC and must mature to present antigens to T-cell receptors. During DC maturation, nuclear factor-κB (NF-κB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-κB proteins and examined its immunoregulatory effects on human monocyte-derived DC (Mo-DC). Regulatory Mo-DC were generated by pretreatment with DHMEQ before LPS stimulation, which were termed dl-DC. DHMEQ pretreatment (5 μg/ml) completely inhibited nuclear translocation of activated NF-κB. DHMEQ significantly inhibited DC production of κproinflammatory cytokines (IL-6, TNF-α, and IL-12 p70) in a dose-dependent manner. IL-12 was most potently inhibited. However, IL-10 production by dl-DC was only moderately affected by DHMEQ. Although CD40 and the expression of HLA-DR (HLA-DR) expression on dl-DC was downregulated, CD80 and CD86 expression was moderately upregulated. Induction of T helper 1 cell responses was efficiently impaired by dl-DC. This confirmed that DHMEQ-treated Mo-DC exhibited immunoregulatory effects. These findings suggest that DHMEQ has potential as an immunosuppressive drug for human immune cells.
AB - Regulation of antigen-presenting cells (APC) is crucial in controlling allograft rejection. Dendritic cells (DC) are the most potent APC and must mature to present antigens to T-cell receptors. During DC maturation, nuclear factor-κB (NF-κB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-κB proteins and examined its immunoregulatory effects on human monocyte-derived DC (Mo-DC). Regulatory Mo-DC were generated by pretreatment with DHMEQ before LPS stimulation, which were termed dl-DC. DHMEQ pretreatment (5 μg/ml) completely inhibited nuclear translocation of activated NF-κB. DHMEQ significantly inhibited DC production of κproinflammatory cytokines (IL-6, TNF-α, and IL-12 p70) in a dose-dependent manner. IL-12 was most potently inhibited. However, IL-10 production by dl-DC was only moderately affected by DHMEQ. Although CD40 and the expression of HLA-DR (HLA-DR) expression on dl-DC was downregulated, CD80 and CD86 expression was moderately upregulated. Induction of T helper 1 cell responses was efficiently impaired by dl-DC. This confirmed that DHMEQ-treated Mo-DC exhibited immunoregulatory effects. These findings suggest that DHMEQ has potential as an immunosuppressive drug for human immune cells.
KW - Dendritic cells
KW - Immunoregulation
KW - NF-κB inhibitor
UR - http://www.scopus.com/inward/record.url?scp=77954761223&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77954761223&partnerID=8YFLogxK
U2 - 10.1016/j.humimm.2010.05.009
DO - 10.1016/j.humimm.2010.05.009
M3 - Article
VL - 71
SP - 763
EP - 770
JO - Human Immunology
JF - Human Immunology
SN - 0198-8859
IS - 8
ER -