Higuchi Toshio, Watanabe Yoshihiro, Waga Iwao
Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Yokohama, Kanagawa, Japan.
Biochem Biophys Res Commun. 2004 May 21;318(1):46-52. doi: 10.1016/j.bbrc.2004.04.002.
We report here that the transcriptional activity of NF-kappaB is negatively regulated by protein disulfide isomerase (PDI). Over-expression of PDI in RAW 264.7 cells strongly suppressed the LPS-induced production of inflammatory cytokines as well as NF-kappaB-dependent luciferase activity. This negative regulation of NF-kappaB was reversed by bacitracin, a PDI inhibitor. Interestingly, NF-kappaB/DNA complex formation and phosphorylation of NF-kappaB subunits was intact in PDI-expressing cells following stimulation with LPS. In addition, PDI and another redox regulator, thioredoxin (TRX), had opposite effects on NF-kappaB-dependent gene expression: activation of the NF-kappaB pathway by TRX was suppressed by expression of PDI in a dose-dependent manner. Finally, PDI expression was induced by the anti-inflammatory cytokine IL-10, and IL-10-mediated inhibition of LPS-induced IL-6 expression was reduced by bacitracin. These findings clearly demonstrate that PDI is a negative regulator of NF-kappaB, and may act downstream of IL-10 in this signaling pathway.
我们在此报告，蛋白二硫键异构酶（PDI）对核因子-κB（NF-κB）的转录活性具有负调控作用。在RAW 264.7细胞中过表达PDI可强烈抑制脂多糖（LPS）诱导的炎性细胞因子产生以及NF-κB依赖的荧光素酶活性。这种对NF-κB的负调控作用可被PDI抑制剂杆菌肽逆转。有趣的是，在用LPS刺激后，表达PDI的细胞中NF-κB/DNA复合物的形成以及NF-κB亚基的磷酸化并未受到影响。此外，PDI和另一种氧化还原调节因子硫氧还蛋白（TRX）对NF-κB依赖的基因表达具有相反的作用：TRX对NF-κB途径的激活可被PDI的表达以剂量依赖的方式抑制。最后，抗炎细胞因子白细胞介素-10（IL-10）可诱导PDI表达，而杆菌肽可降低IL-10介导的对LPS诱导的白细胞介素-6（IL-6）表达的抑制作用。这些发现清楚地表明，PDI是NF-κB的负调控因子，并且可能在该信号通路中位于IL-10的下游发挥作用。
