Regulation of human dendritic cells by a novel specific nuclear factor-kappaB inhibitor, dehydroxymethylepoxyquinomicin.

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-kappaB (NF-kappaB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-kappaB 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 microg/ml) completely inhibited nuclear translocation of activated NF-kappaB. DHMEQ significantly inhibited DC production of proinflammatory cytokines (IL-6, TNF-alpha, 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.

Shinoda K ，Nakagawa K ，Kosaka T ，Tanaka N ，Maeda T ，Kono H ，Mizuno R ，Kikuchi E ，Miyajima A ，Umezawa K ，Oya M ... -  《-》

Differential roles of PI3-Kinase, MAPKs and NF-kappaB on the manipulation of dendritic cell T(h)1/T(h)2 cytokine/chemokine polarizing profile.

Neves BM ，Cruz MT ，Francisco V ，Garcia-Rodriguez C ，Silvestre R ，Cordeiro-da-Silva A ，Dinis AM ，Batista MT ，Duarte CB ，Lopes MC ... -  《-》

Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo.

Matsumoto G ，Namekawa J ，Muta M ，Nakamura T ，Bando H ，Tohyama K ，Toi M ，Umezawa K ... -  《CLINICAL CANCER RESEARCH》

Control of allograft rejection by applying a novel nuclear factor-kappaB inhibitor, dehydroxymethylepoxyquinomicin.

Ueki S ，Yamashita K ，Aoyagi T ，Haga S ，Suzuki T ，Itoh T ，Taniguchi M ，Shimamura T ，Furukawa H ，Ozaki M ，Umezawa K ，Todo S ... -  《TRANSPLANTATION》

Antitumor effects of the novel NF-kappaB inhibitor dehydroxymethyl-epoxyquinomicin on human hepatic cancer cells: analysis of synergy with cisplatin and of possible correlation with inhibition of pro-survival genes and IL-6 production.

Poma P ，Notarbartolo M ，Labbozzetta M ，Sanguedolce R ，Alaimo A ，Carina V ，Maurici A ，Cusimano A ，Cervello M ，D'Alessandro N ... -  《INTERNATIONAL JOURNAL OF ONCOLOGY》