Malloapelta B suppresses LPS-induced NF-κB activation and NF-κB-regulated target gene products
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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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NF-κB는 anti-apoptotic gene을 유도하는 전사인자로서 대부분의 세포의 생존에 필요하다. 그러나 NF-κB가 많은 종류의 암세포에서 지속적으로 과다 활성화됨이 알려지면서 NF-κB의 활성억제가 암의 예방과 치료에 유효하다는 점이 알려지게 되었다. 한편, Hsp70가 NF-κB의 활성을 조절한다는 사실이 알려지면서 Hsp70를 이용한 암예방과 치료가 주목받게 되었으나 아직 Hsp70에 의한 NF-κB의 활성조절기전은 명확하지 않다. 본 연구에서는 Hsp70에 의한 NF-κB의 활성조절과정에서 IKK complex의 구성성분인 IKKγ의 역할을 검토하였다. IKKγ의 wild type과 deletion mutants를 이용하여 Hsp70와 관련된 NF-κB의 활성조절을 연구한 결과 Hsp70는 NF-κB의 활성화를 억제하였으며, 이러한 억제효과는 IKKγ가 과발현되었을 때 더욱 증가하였다. 또한 IKKγ의 N-말단의 IKKβ 결합부위와 C-말단의 Leucine zipper 및 Zinc finger부위는 Hsp70와 연관된 NF-κB억제작용에 필요하지 않는 것으로 나타났으며, Hsp70와 IKKγ에 의한 NF-κB의 활성억제는 IκBα의 인산화와 분해를 저해함에 의해 일어나는 것으로 나타났다. 또한 RAW264.7 macrophage세포에서 LPS에 의한 COX-2의 발현유도는 Hsp70와 IKKγ가 동시에 발현 되었을 때 가장 효과적으로 억제되었다. 이상의 결과로부터 Hsp70에 의한 NF-κB의 활성억제작용은 IKKγ에 의해 상승됨을 알 수 있었으며, Hsp70와 IKKγ를 적절히 이용하면 NF-κB의 과다활성에 의해 발생하는 각종 질병의 예방과 치료에 도움을 줄 수 있을 것으로 기대된다. NF-κB acts as a critical transcription factor for the survival of cells via the induction of antiapoptotic genes. Constitutive activation of NF-κB in many types of solid tumors suggests that the inhibition of NF-κB might prevent or inhibit tumorigenesis. Although a number of studies demonstrated that Hsp70 regulated NF-κB activity, the exact mechanism is not clear. This study investigated the functional relationship of Hsp70 and IKKγ in the regulation of NF-κB activation using expression plasmids of components of the IKK complex. Wild-type and deletion mutants of IKKγ were expressed together with Hsp70, and the combined regulatory effect of Hsp70 and IKKγ on NF-κB activation was assayed. Hsp70 suppressed the activation of NF-κB in a reporter plasmid assay. Hsp70 also suppressed the phosphorylation and degradation of IκBα. The suppressive effect of Hsp70 on NF-κB activation was synergistically elevated by IKKγ. The N-terminal IKKβ binding site, C-terminal leucine zipper, and zinc finger domains of IKKγ were not necessary for the suppressive effect. Furthermore, Hsp70 and IKKγ synergistically suppressed the induction of COX-2 expression by lipopolysaccharides in RAW264.7 cells. These results suggest that overexpression of Hsp70 and IKKγ may be a strategic method for inhibition of NF-κB and related diseases.
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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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Cigarette smoke (CS), a major risk factor for developing lung cancer, is known to activate transcriptional activator nuclear factor kappa B (NF-κB). However, the underlying mechanism of this activation remains unclear because of conflicting reports. As NF-κB has a pivotal role in the generation and maintenance of malignancies, efforts were targeted towards understanding its activation mechanism using both ex vivo and in vivo studies. The results show that CS-induced NF-κB activation mechanism is different from that of other pro-inflammatory signals such as lipopolysaccharide (LPS). The NF-κB dimer that translocates to the nucleus upon stimulation with CS is predominantly composed of c-Rel/p50 and this translocation involves degradation of I-κBɛ and not I-κBα. This degradation of I-κBɛ depends on IKKβ activity, which preferentially targets I-κBɛ. Consistently, CS-activated form of IKKβ was found to be different from that involved in LPS activation as neither Ser177 nor Ser181 of IKKβ is crucial for CS-induced NF-κB activation. Thus, unlike other pro-inflammatory stimulations where p65 and I-κBα have a central role, the predominantly active signaling cascade in CS-induced NF-κB activation in the lung epithelial cells comprises of IKKβ-I-κBɛ-c-Rel/p50. Thus, this study uncovers a new axis of NF-κB activation wherein I-κBɛ and c-Rel have the central role.
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Modulation of nuclear factor-kappa B (NF-κB) expression has important clinical implications including anti-inflammation. Recently, we have shown that direct regulation of NF-κB/p65 subunit may account for tacrolimus ointment's remarkable clinical efficacy on treating inflammatory dermatoses. However, NF-κB is a dimeric transcription factor formed by hetero- or homodimeration of the five Rel family proteins. The complete operational scheme of different NF-κB subunits remains obscure. It has been shown that homodimers consist of NF-κB/p50 may serve an inhibitory role in suppressing inflammation while dimers consisting of NF-κB/p65 activate inflammatory pathway. Our current study aimed to explore the effects of ultraviolet B (UVB) on epidermal keratinocytes in terms of specific NF-κB subunits NF-κB/p50 and NF-κB/p65. Additionally, the effects of tacrolimus on differential regulation of NF-κB subunits of UVB irradiated keratinocytes were also investigated. Our result showed that UVB sequentially regulated the activities of different subunits of NF-κB: the activity of NF-κB/p50 was downregulated in the early stage (6 hours), followed by upregulation of NF-κB/p65 in the later stage (12 hours). The results from immunofluorescence, immunocytochemical, and immunohistochemical analyses indicated that the nuclear expression of NF-κB/p50 could be seen constitutively while the nuclear expression of NF-κB/p65 could only be seen after UVB irradiation. Furthermore, treatment with tacrolimus didn't affect the nuclear activation and translocation of NF-κB/p50, while the UVB induced NF-κB/p65 nuclear expression was suppressed by tacrolimus. In summary, we have shown that UVB irradiation sequentially regulated different NF-κB subunits. The clinical efficacy of tacrolimus may be attributed to its specific regulatory effect on NF-κB/p65 but not NF-κB/p50 of the NF-κB pathway.
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It is well documented that ionizing radiation (IR) activates the transcription factor (NF-κB) which is a trigger for resistance cancer cells to treatment. It is involved in activation of pro-survival signaling pathways and resulting in cancer development and progression. In unstimulated condition, NF-κB is sequestered in cytoplasm but after the cell exposure to IR, proteasomal degradation of IκB flowing phosphorylation via IKK, leads to aberrantly NF-κB activation and nuclear translocation. Therefore, interruption in IκB degradation, proteasome action, IKK phosphorylation and NF-κB nuclear translocation provide robust strategies for inhibiting adverse effect of IR induced NF-κB. In spite of uncompleted elucidation of NF-κB molecular mechanisms, different NF-κB inhibitors have been used in order to inhibiting the IR induced NF-κB. The aim of this review is to highlight the role of IR induced-NF-κB inhibitors such as MG132, bortezomib, curcumin, DHMEQ, naringin, sorafenib, genistein and parthenolide in suppression of IR induced NF-κB adverse effects. Moreover, their chemical, structural characteristics and molecular mechanisms will be discussed.
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