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NF-κB のシグナル伝達(パスウェイ)とその制御にはさまざまなタンパク質が関与しており、それらタンパク質それぞれに、阻害もしくは活性化する低分子化合物(生理活性物質)が知られています。このような化合物を以下の表にまとめました。
分類 | 低分子化合物 | 活性 | IC50 | 参考文献 |
IKK 複合体阻害 | IκB の分解と IL-8 の発現をブロックする IKK 阻害剤 | 400 nM (IKKα)、17.9 nM (IKKβ) | 1,2 | |
IKKβ 阻害剤で、NOS、COX-2、IL-1β、IL-6 などの発現を抑制する | 1 μM (RAW 264.7 細胞) | 3 | ||
高選択性 IKKα 阻害剤 | 4 μM (IKKα)、 0.3 µM(IKKβ) | 4 | ||
臨床でも使用される IKKε および TBK-1 阻害剤 | 1-2 μM(IKKε) | 5 | ||
可逆的な、ATP 競合 IKKβ 選択的阻害剤 | 10.2 μM | 6,7 | ||
強力な IKKβ 選択的阻害剤 | 250 nM | 8 | ||
強力な IKK 選択的阻害剤で、NOS の発現を抑制する | 25 nM | 9,10 | ||
IκB 分解阻害 | IκB へのユビキチン付加を阻害する | 10 μM | 11,12 | |
強力で可逆的なプロテアソーム阻害剤であり、RANKL シグナリングを妨害する | 97.5 nM | 13,14 | ||
22.4 nM | 14 | |||
強力な不可逆的 20S プロテアソーム阻害剤 | 0.2-2.8 μM | 15 | ||
6.8 nM | 14 | |||
IκBα 分解と IKK 複合体の活性を阻害する | 30 μM | 12 | ||
強力な不可逆的 26S プロテアソーム阻害剤 | 8.32-16.55 nM | 16 | ||
強力な Nedd-8(Ubiquitin-like protein)活性化酵素阻害剤 | 4.7 nM | 17,18 | ||
NF-κB 核移行阻害 | in vivo および LPS 処理した RAW264.7 細胞で、NF-κB の核移行を阻害する | - | 19,20 | |
LPS 処理した 絨毛膜細胞で、NF-κB の核移行を阻害する | - | 21 | ||
p65 アセチル化阻害 | LPS 処理した A549 細胞で、p65 のアセチル化を阻害する | 76 μM | 22,34 | |
4 µM TNF 処理した KBM-5 細胞で、p65 のアセチル化を阻害する | - | 23 | ||
NF-κB-DNA 結合 | NF-κB が RANTES や IL-8 のプロモーターに結合するのを抑制する | - | 24 | |
p50-Cys62 に作用することにより、NF-κB の DNA への結合を阻害する | 500 nM | 25 | ||
p65 の DNA 結合を阻害する PAFR アンタゴニスト | - | 26 | ||
p50-p65 サブユニットの核輸送を阻害する | - | 27 | ||
NF-κB 転写活性阻害 | IL-1 刺激後のNF-κB による転写活性化をブロックする | - | 28,29 | |
p65 による転写活性化を阻害する | - | 30 | ||
p53 誘導 | NF-κB とその下流の転写ターゲットを下方制御する | 5 μM(RKO 細胞) | 31,32 | |
TNFα 誘導性の NF-κB 活性化を阻害する | 1 μM (HT29 細胞) | 33 | ||
NF-κB 活性化または誘導 | NF-κB(p65)の核移行を促進し、転写活性を強める | - | 35 | |
カルシニューリンと相乗的に NF-κB の活性化を誘導する | - | 36 | ||
NF-κB の DNA への結合を促す | - | 37,38 | ||
NF-κB のアクチベーターであり、Ca2+ イオノフォアでもある | - | 39 |
抗酸化物質
PDTC40 や NAC41 のような抗酸化物質は、LPS、TNFα、過酸化水素などの刺激による NF-κB の活性化を阻害する能力があることが示されています。これら抗酸化物質は NF-κB パスウェイ中にある活性酸素中間体を補足することによって NF-κB を阻害すると思われます42。
抗炎症剤と免疫抑制剤
広く利用されている非ステロイド性抗炎症薬(NSAID)であるサリチル酸ナトリウム(Sodium salicylate)は IKKβと結合し43、IκB のプロテアソームによる分解を阻害することが示されています44。また免疫調節機能があるグルココルチコイド系ステロイド、デキサメタゾン(Dexamethasone; DEX)は、NF-κB の活性化を阻害し、TNFα の産生を抑制することが知られています45,46。
免疫抑制の研究から、免疫抑制剤として市販されているシクロスポリン A(Cyclosporin A; CsA)は、NF-κB /RelA の活性化を阻害し、IL-2 と IL-8 の発現を抑制することが示されています47,48。また、市販されている別の免疫抑制剤である FK506(Tacrolimus; タクロリムス)は、p50 の核移行をブロックすることにより、下流にある IL-2 などの炎症性サイトカイン遺伝子の転写活性化を抑制することが示されています49。
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