Reduced infiltration and increased apoptosis of leukocytes at sites of inflammation by systemic administration of a membrane-permeable IkappaBalpha repressor.
Reduced infiltration and increased apoptosis of leukocytes at sites of inflammation by systemic administration of a membrane-permeable IkappaBalpha repressor.
复制标题
通过全身施用膜可渗透的Ikappabalpha抑制剂，炎症部位的浸润减少和白细胞凋亡增加。
DOI：
10.1002/art.20467
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发表时间：
2004-08
影响因子：
--
通讯作者：
Kabouridis, Panagiotis S
中科院分区：
文献类型：
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作者：
Blackwell, Nathan M;Sembi, Phupinder;Newson, Justine S;Lawrence, Toby;Gilroy, Derek W;Kabouridis, Panagiotis S
NF-κB活化与包括类风湿关节炎（RA）在内的多种炎症性疾病有关，这使得该转录因子家族成为抗炎治疗开发的良好靶点。虽然NF-κB通路的抑制剂目前可用，但其特异性尚未充分确定。i -κB α是NF-κB的生理性抑制剂，在实验中以不可降解的形式表达时是一种有效的抑制因子。我们在此描述了一种在体内特异性调节NF-κB活性的新方法，即通过将含有超抑制因子i -κB α (sri -κB α)的嵌合分子融合到人类免疫缺陷病毒Tat蛋白（Tat- sri -κB α）的膜转导结构域来调节NF-κB活性。采用Wistar大鼠卡拉胶胸膜炎模型，研究体内给药at- sri - κ b α对胸膜炎大鼠白细胞浸润及细胞因子和趋化因子产生的影响。全身给予tat - sri - κ b α可减少白细胞向炎症部位的浸润。对募集的炎症细胞的分析证实了抑制剂的摄取和NF-κB活性的降低。这些细胞表现出升高的caspase活性，表明NF-κB是炎症部位白细胞存活所必需的。对渗出液的分析显示，虽然促炎细胞因子肿瘤坏死因子α和白细胞介素-1β的产生减少，但与对照组相比，中性粒细胞趋化剂细胞因子诱导的中性粒细胞趋化剂1 （cinc1）和cinc3的产生也显著增加。这一结果可能揭示了一种以前未知的反馈机制，其中浸润的白细胞可能下调这些趋化因子的局部产生。这些结果为炎症的病因学提供了新的见解，并通过调节已知在RA中起作用的途径的信号活性，为开发新的治疗方法建立了策略。
NF-κB activation is associated with several inflammatory disorders, including rheumatoid arthritis (RA), making this family of transcription factors a good target for the development of antiinflammatory treatments. Although inhibitors of the NF-κB pathway are currently available, their specificity has not been adequately determined. IκBα is a physiologic inhibitor of NF-κB and a potent repressor experimentally when expressed in a nondegradable form. We describe here a novel means for specifically regulating NF-κB activity in vivo by administering a chimeric molecule comprising the super-repressor IκBα (srIκBα) fused to the membrane-transducing domain of the human immunodeficiency virus Tat protein (Tat-srIκBα). The Wistar rat carrageenan-induced pleurisy model was used to assess the effects of in vivo administration of Tat-srIκBα on leukocyte infiltration and on cytokine and chemokine production. Systemic administration of Tat-srIκBα diminished infiltration of leukocytes into the site of inflammation. Analysis of the recruited inflammatory cells confirmed uptake of the inhibitor and reduction of the NF-κB activity. These cells exhibited elevated caspase activity, suggesting that NF-κB is required for the survival of leukocytes at sites of inflammation. Analysis of exudates, while showing decreases in the production of the proinflammatory cytokines tumor necrosis factor α and interleukin-1β, also revealed a significant increase in the production of the neutrophil chemoattractants cytokine-induced neutrophil chemoattractant 1 (CINC-1) and CINC-3 compared with controls. This result could reveal a previously unknown feedback mechanism in which infiltrating leukocytes may down-regulate local production of these chemokines. These results provide new insights into the etiology of inflammation and establish a strategy for developing novel therapeutics by regulating the signaling activity of pathways known to function in RA.