An additional long-term mechanism of NF-κB regulation after cytokine treatment in a human hepatoma cell line
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AbstractThe transcription factor NF-κB was first identified as a regulator of the expression of the kappa light-chain gene in murine B lymphocytes (1). It has a central role in the immunological processes and regulates a wide range of genes in a rapid fashion (2). NF-κB interacts with its inhibitor protein IκB and activation of NF-κB causes it to move into the nucleus and this is controlled by the phosphorylation and subsequent degredation of IκB (3,4). The activated form of NF-κB is a heterodimer, which usually consists of two proteins, a p65 (relA) subunit and a p50 subunit. Other subunits (rel, relB, v-rel, and p52) can also bind to the activated NF-κB and thus can activate different sets of genes.KeywordsLabel OligonucleotideP47phox SubunitHela Nuclear ExtractRapid FashionFollow Glucose IntakeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Abstract Purpose: Deoxyelephantopin (ESD) and isodeoxyelephantopin (ESI) are two sesquiterpene lactones derived from the medicinal plant Elephantopus scaber Linn. (Asteraceae). Although they are used for the treatment of a wide variety of proinflammatory diseases, very little is known about their mechanism of action. Because most genes that control inflammation are regulated by activation of the transcription factor nuclear factor-κB (NF-κB), we postulated that ESD and ESI mediate their activities through modulation of the NF-κB activation pathway. Experimental Design: We investigated the effect of ESI and ESD on NF-κB activation by electrophoretic mobility shift assay and NF-κB-regulated gene expression by Western blot analysis. Results: We found that ESI suppressed NF-κB activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1β, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-κB activation was blocked. ESI did not interfere with the binding of NF-κB to DNA but rather inhibited IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-κB-regulated, proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of apoptosis induced by TNF and suppression of TNF-induced invasion and receptor activator of NF-κB ligand-induced osteoclastogenesis. Conclusion: Our results indicate that ESI inhibits NF-κB activation and NF-κB-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.
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Parthenolide (PTN ) ，一个选择原子因素 kappa B (NF-B ) 禁止者，广泛地被使用了禁止 NF-B 激活。在 vivo 的 NF-B 上的 PTN 的禁止的效果的持续时间仍然保持不清楚。这研究是决定是否在 PTN 的管理以后的 6， 12 和 24 h 能激活的 lipopolysaccharide (LPS ) 挑战 NF-B。老鼠是进五个组的 devided。在 PTN， PTN+LPS 和 DMSO 组的老鼠与 PTN 或 DMSO intraperitoneally 被注射。在 6， 12 或 24 h 以后， LPS 在 LPS 和 PTN+LPS 组被管理。NF-B p50， IB 和 p-IB 的表情在 24 h 在 6 和 12 h 和没有效果的结束在 PTN 和 PTN+LPS 组被禁止。在摘要，心肌的 NF-B 表示发生在 LPS 的管理以后的 1 h。PTN 堵住在 6 h 给的这效果和没有禁止的效果在在 vivo 的管理以后的 24 h。
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Objective: The NO production through the iNOS induction by activation of nuclear factor (NF-κB) is known to involve in various inflammatory conditions. Sanggenon C and O, two Diels-Alder type adducts isolated from Morus alba, a plant has been used for the anti-inflammatory purpose in the Oriental medicine, were investigated for their effect on the NO production, iNOS expression and NF-κB activity.Methods: The inhibitory effects of sanggenon C and O on the NF-κB activity were investigated in LPS-stimulated RAW264.7 cells by SEAP reporter assay. The regulation of the iNOS expression and IκBα activation by two compounds was also evaluated by Western blot.Results: Both compounds strongly inhibited NO production and NF-κB activation in a dose-dependent manner. The expression of the iNOS protein was also suppressed by treatment of the compounds (10 and 1 µM). Sanggenon O showed stronger inhibition than the diastereomer sanggenon C. Both compounds prevented the phosphorylation and degradation of IκBα protein.Conclusion: We demonstrated that sanggenon C and O inhibited NO production and iNOS expression by suppressing NF-κB activity and IκBα activation.
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In un-stimulated cells, transcription factor NF-κB is kept in cytoplasm through interaction with IκB inhibitory proteins. Exposure to inducers stimuli results in IκB phosphorylation and ubiquitilation. Liberated NF-κB is trans-located to the nucleus and bind to DNA, where they regulate the expression of a wide variety of genes. Recent studies have indicated that the NF-κB plays a central role in the regulation of inflammatory diseases and the study of the regulation of NF-κB pathways will provide a platform for developing specific therapy for inflammatory diseases.
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