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Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1)-induced NF-κB activation is essential for EBV-transformed B cell
survival. LMP1 has two C-terminal cytoplasmic domains referred to as C-Terminal Activation Regions (CTAR) 1 and 2 that activate
the alternative and canonical NF-κB pathways, respectively. While CTAR2 activates TRAF6, IKKβ and IKKγ-dependent canonical
NF-κB pathway, CTAR1 interacts with TRAF2 and TRAF3 and activates NIK and IKKα-dependent alternative NF-κB pathway involving
p100 processing into functional p52. Using IKKα−/−, IKKβ−/−, IKKγ−/−, TRAF2−/−, TRAF3−/−, TRAF6−/−, and NIKaly/aly mouse embryonic fibroblasts (MEFs), potential roles of these proteins in LMP1-induced alternative NF-κB activation were investigated.
Deficiency in IKKα or functional NIK, but not in IKKβ, IKKγ, or TRAF6, severely impaired LMP1-induced p100 processing. Notably,
p100 was constitutively processed in TRAF2−/− or TRAF3−/− MEFs independently of LMP1 suggesting that TRAF2 or TRAF3 may play a regulatory role in p100 processing. Subsequently, TRAF2
or TRAF3 over-expression in HEK293 cells significantly blocked LMP1-induced p100 processing. The LMP1 CTAR1 expression in
293HEK cells activated the alternative p65/p52 complex while CTAR2 failed to do so. Taken together, LMP1 activates alternative
NF-κB pathway through functional NIK and IKKα that is regulated by TRAF2 or TRAF3. 相似文献
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AIM: To investigate the role of nuclear factor κB(NF-κB) in the regulation of Epstein-Barr virus(EBV) latent membrane protein 1(LMP1) in EBV transformed cells. METHODS: LMP1 expression was examined in EBV transformed human B lymphocytes with modulation of NF-κB activity. RESULTS: EBV infection is associated with several human cancers. EBV LMP1 is required for efficient transformation of adult primary B cells in vitro, and is expressed in several pathogenic stages of EBVassociated cancers. Regulation of EBV LMP1 involves both viral and cellular factors. LMP1 activates NF-κB signaling pathway that is a part of the EBV transformation program. However, the relation between NF-κB and LMP1 expression is not well established yet. In this report, we found that blocking the NF-κB activity by Inhibitor of κB stimulated LMP1 expression, while the overexpression of NF-κB repressed LMP1 expression in EBV-transformed IB4 cells. In addition, LMP1 repressed its own promoter activities in reporter assays, and the repression was associated with the activation of NF-κB. Moreover, NF-κB alone is sufficient to repress LMP1 promoter activities. CONCLUSION: Our data suggest LMP1 may repress its own expression through NF-κB in EBV transformed cells and shed a light on LMP1 regulation during EBV transformation. 相似文献
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Mayu Morishita Kyoko Arimoto-Matsuzaki Masami Kitamura Kyohei Niimura Hiroaki Iwasa Junichi Maruyama Yuichi Hiraoka Kohei Yamamoto Masanobu Kitagawa Norio Miyamura Hiroshi Nishina Yutaka Hata 《Genes to cells : devoted to molecular & cellular mechanisms》2021,26(12):999-1013
RASSF6 is a member of the tumor suppressor Ras association domain family (RASSF) proteins. We have reported using human cancer cell lines that RASSF6 induces apoptosis and cell cycle arrest via p53 and plays tumor suppressive roles. In this study, we generated Rassf6 knockout mice by CRISPR/Cas technology. Contrary to our expectation, Rassf6 knockout mice were apparently healthy. However, Rassf6-null mouse embryonic fibroblasts (MEF) were resistant against ultraviolet (UV)-induced apoptosis/cell cycle arrest and senescence. UV-induced p53-target gene expression was compromised, and DNA repair was delayed in Rassf6-null MEF. More importantly, KRAS active mutant promoted the colony formation of Rassf6-null MEF but not the wild-type MEF. RNA sequencing analysis showed that NF-κB signaling was enhanced in Rassf6-null MEF. Consistently, 7,12-dimethylbenz(a)anthracene (DMBA) induced skin inflammation in Rassf6 knockout mice more remarkably than in the wild-type mice. Hence, Rassf6 deficiency not only compromises p53 function but also enhances NF-κB signaling to lead to oncogenesis. 相似文献
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Pan X Cao H Lu J Shu X Xiong X Hong X Xu Q Zhu H Li G Shen G 《Molecular immunology》2011,48(12-13):1573-1577
HBV replicates noncytopathically in hepatocytes, but HBV or proteins encoded by HBV genome could induce cytokines, chemokines expression by hepatocytes. Moreover, liver damage in patients with HBV infection is immune-mediated and cytokines play important roles in immune-mediated liver damage after HBV infection. Interleukin-32 (IL-32) is a proinflammatory cytokine and plays a critical role in inflammation. However, the role of HBV in IL-32 expression remains unclear. In the present study, we demonstrate that hepatitis B virus protein X (HBx) increases IL-32 expression through the promoter of IL-32 at positions from -746 to +25 and in a dose-dependent manner. Furthermore, we demonstrate that increase of NF-κB subunits p65 and p50 in Huh7 cells also augments IL-32 expression, and the NF-κB inhibitor blocks the effect of HBx on IL-32 induction. These results indicate that NF-κB activation is required for HBx-induced IL-32 expression. In conclusion, IL-32 is induced by HBx in Huh7 cells. Our results suggest that IL-32 might play an important role in inflammatory response after HBV infection. 相似文献
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Fujiang Cao Tao Liu Yunqiang Xu Dongdong Xu Shiqing Feng 《International journal of clinical and experimental pathology》2015,8(6):6037-6045
Curcumin is a polyphenol compound extracted from ginger plant, turmeric, commonly used in a variety of food coloring and flavoring additives. Curcumin has many effects such as anti-inflammatory, anti-tumor, antioxidant and anti-microbial effects. However, the mechanism underlying the anti-cancer effect of curcumin on human osteoclastoma (Giant cell tumor, GCT) cells remains unclear. The objectives of this study were to determine the efficacy of curcumin on proliferation and apoptosis of GCT cells and its related mechanisms. In our study, cell viability, cellular apoptosis and caspase-3 activity of GCT cells were analyzed using 3.3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry (FCM) assay and commercial kits, respectively. Next, MMP-9 gene expression quantity, NF-κB activity and JNK protein expression of GCT cells were tested with real-time polymerase chain reaction (RT-PCR), commercial kits and western blotting assay, respectively. Firstly, MMP-9, NF-κB and JNK inhibitors were added into GCT cells and which was researched the mechanism of curcumin on human GCT cells. In this study, the efficacy of curcumin reduced cell viability, induced cellular apoptosis and increased caspase-3 activity of GCT cells. Furthermore, curcumin inhibited the MMP-9 gene expression quantity and NF-κB activity, and activated JNK protein expression in GCT cells. Meanwhile, down-regulation of MMP-9 gene expression quantity and NF-κB activity could promote the anti-cancer effect of curcumin on cell viability of GCT cells. Interesting, down-regulation of JNK protein expression could also reversed the anti-cancer effect of curcumin on cell viability of GCT cells. Taken together, our results suggest that curcumin inhibits cell proliferation and promotes apoptosis in osteoclastoma cell through suppression of MMP-9 and NF-κB, and activation JNK signaling pathways. 相似文献
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Xia X Cui J Wang HY Zhu L Matsueda S Wang Q Yang X Hong J Songyang Z Chen ZJ Wang RF 《Immunity》2011,34(6):843-853
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In situ glomerular expression of activated NF-κB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy 总被引:1,自引:0,他引:1
Zheng L Sinniah R Hsu SI 《Virchows Archiv : an international journal of pathology》2006,448(2):172-183
Nuclear Factor-κB (NF-κB) has been suggested to play a role in the cellular and molecular mechanisms underlying glomerular
injury. We investigated the potential role of NF-κB activation in the pathogenesis of glomerular injury in 31 patients with
class III–V lupus nephritis (LN), 14 patients with non-proliferative proteinuric glomerulopathy and six normal controls. The
expression of NF-κB subunits p65 and p50, and the NF-κB regulated proinflammatory mediators tumor necrosis factor-α (TNF-α),
interleukin-1β (IL-1β), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) as well as CD68 and synaptopodin
was examined by Southwestern histochemistry (SWH) or immunohistochemistry. In contrast to non-proliferative glomerulopathy
and normal controls, NF-κB activation (both p65 and p50) was enhanced in glomerular endothelial, mesangial cells or infiltrating
cells in class IV LN, along with upregulation of TNF-α, IL-1β, IL-6 and ICAM-1 expression. Glomerular endothelial and mesangial
activation of NF-κB and mesangial ICAM-1 expression correlated with disease activity and the level of glomerular macrophage
infiltration. Podocyte NF-κB overactivation (predominantly p65) paralleled podocyte expression of TNF-α and IL-1β in patients
with LN and non-proliferative glomerulopathy. Podocyte staining scores of NF-κB and p65 were positively correlated with the
severity of proteinuria in LN and non-proliferative glomerulopathy. These results suggest a pathogenic role for NF-κB in glomerular
injury by multiple mechanisms. 相似文献
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Lijia Liu Jianchun Li Joydeb Kumar Kundu Young-Joon Surh 《Inflammation research》2014,63(12):1013-1021
Objectives
The present study was aimed at elucidating the molecular mechanisms of anti-inflammatory activity of piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene) in mouse skin in vivo.Methods
Female HR-1 hairless mice were topically treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) with or without piceatannol pretreatment. Epidermal protein expression was assessed by Western blot analysis. The cyclooxygenase-2 (COX-2) expression was detected by immunohistochemistry. The DNA binding of nuclear factor-kappaB (NF-κB) and activator protein-1 (AP-1) was examined by the electrophoretic mobility gel shift assay. The catalytic activity of IκBα kinase-β (IKKβ) was measured by in vitro kinase assay.Results
Pretreatment with piceatannol attenuated TPA-induced expression of COX-2 and inducible nitric oxide synthase (iNOS) in mouse skin. Piceatannol diminished nuclear translocation and the DNA binding of NF-κB through the blockade of phosphorylation and subsequent degradation of IκBα. Piceatannol attenuated the catalytic activity of IKKβ and inhibited the phosphorylation of mitogen-activated protein (MAP) kinases in TPA-treated mouse skin. In addition, piceatannol decreased TPA-induced expression of c-Fos and the DNA binding of AP-1.Conclusion
Piceatannol inhibits TPA-induced COX-2 and iNOS expression by blocking the activation of NF-κB and AP-1 via suppression of the IKKβ activity and phosphorylation of MAP kinases, which provides a mechanistic basis of its anti-inflammatory effects in mouse skin. 相似文献16.
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Chen P Shi Q Xu X Wang Y Chen W Wang H 《International journal of molecular medicine》2012,30(1):119-125
Diabetic nephropathy (DN), which is characterized by mesangial cell proliferation, is a common complication observed in diabetic patients. The protective effects of quercetin for DN have been reported; however, the mechanism has yet to be determined. We aimed to identify the underlying mechanism for quercetin protection against DN. High glucose (HG)-induced human mesangial cell (HMC) proliferation, a feature of the early stages of diabetic nephropathy, was employed as an in vitro model. Cells were grown in normal glucose (5.6 mM), high glucose (30 mM) or high glucose with various concentrations of quercetin. Cell proliferation, cell cycle progression, and expression of NF-κB and MCP-1 were examined by MTT assay, DNA staining, immunocytochemistry and western blot analysis, respectively. HMCs cultured in high glucose had signficantly greater proliferation, accumulation in the G1 phase, upregulated NF-κB and MCP-1 expression. Quercetin treatment reversed the effects of high glucose in a dose-dependent manner. Cotreatment of quercetin with pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB activation, suggest that the effects of quercetin are partially mediated by NF-κB signaling. Quercetin partially suppresses the effects of high glucose in HMC cultures, which are mediated at least in part through the suppression of NF-κB. 相似文献
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Zanjing Zhai Xinhua Qu Haowei Li Ke Yang Peng Wan Lili Tan Zhengxiao Ouyang Xuqiang Liu Bo Tian Fei Xiao Wengang Wang Chuan Jiang Tingting Tang Qiming Fan An Qin Kerong Dai 《Biomaterials》2014
Wear particle-induced aseptic prosthetic loosening is one of the most common reasons for total joint arthroplasty (TJA). Extensive bone destruction (osteolysis) by osteoclasts plays an important role in wear particle-induced peri-implant loosening. Thus, strategies for inhibiting osteoclast function may have therapeutic benefit for prosthetic loosening. Here, we mimicked the process of magnesium (Mg) degradation in vivo and obtained Mg leach liquor (MLL) by immersing pure Mg in culture medium. For the first time, we demonstrated that MLL suppresses osteoclast formation, polarization, and osteoclast bone resorption in vitro. An in vivo assay demonstrated that MLL attenuates wear particle-induced osteolysis. Furthermore, we found that MLL significantly inhibits nuclear factor-κB (NF-κB) activation by retarding inhibitor-κB degradation and subsequent NF-κB nuclear translocation. We also found that MLL attenuates the expression of NFATc1 at both the protein and mRNA levels. These results demonstrate that MLL has anti-osteoclast activity in vitro and prevents wear particle-induced osteolysis in vivo. Collectively, our study suggests that metallic magnesium, one of the orthopedic implants with superior properties, has significant potential for the treatment of osteolysis-related diseases caused by excessive osteoclast formation and function. 相似文献
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Agus Budiawan Naro Putra Kosuke Nishi Ryusuke Shiraishi Mikiharu Doi Takuya Sugahara 《Molecular immunology》2014
We previously reported that jellyfish collagen stimulates both the acquired and innate immune responses. In the acquired immune response, jellyfish collagen enhanced immunoglobulin production by lymphocytes in vitro and in vivo. Meanwhile, in the innate immune response jellyfish collagen promoted cytokine production and phagocytotic activity of macrophages. The facts that jellyfish collagen plays several potential roles in stimulating cytokine production by macrophages have further attracted us to uncover its mechanisms. We herein describe that the cytokine production-stimulating activity of jellyfish collagen was canceled by a Toll-like receptor 4 (TLR4) inhibitor. Moreover, jellyfish collagen stimulated phosphorylation of inhibitor of κBα (IκBα), promoted the translocation of nucleus factor-κB (NF-κB), and activated c-Jun N-terminal kinase (JNK). A JNK inhibitor also abrogated the cytokine production-stimulating activity of jellyfish collagen. These results suggest that jellyfish collagen may facilitate cytokine production by macrophages through activation of NF-κB and JNK via the TLR4 signaling pathways. 相似文献
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Guibin Qian Songnan Hao Dawei Yang Qinggang Meng 《International journal of clinical and experimental pathology》2015,8(11):14885-14892
Primary bone tumor is one of the most common malignant tumors in skeletal system. It seriously affected bone movement and development with unclear pathogenesis. In this paper, rabbit VX-2 malignant bone tumor model was applied to explore apoptotic genes P15, MDM2, NF-κB and Bcl-2 correlation with primary bone tumor occurrence and metastasis. 0.3 ml rabbit VX-2 tumor cell suspension (1×106/ml) was injected to the marrow cavity of the right tibia condyle to establish the rabbit malignant bone tumor model, while equal amount of the saline was injected to the left tibia as control. Real-time PCR was applied to determine P15, MDM2, NF-κB and Bcl-2 expression level. Immunohistochemistry was performed to detect the abovementioned genes expression in lung, stomach, kidney and bladder. Compared with control, P15 expression level in the inoculation site surrounding tissues decreased obviously following the inoculate time elongation (P<0.05), while Bcl-2, MDM2 and NF-κB expression significantly increased (P<0.05). Bcl-2 showed significant correlation with MDM2 and NF-κB (P<0.05). At the 2, 4, 6 weeks, Bcl-2, MDM2 and NF-κB in lung, Bcl-2 in kidney, and Bcl-2 and MDM2 in bladder positively expressed (P<0.05), whereas P15 gene exhibited no significant positive expression in these tissues (P>0.05). P15, MDM2, NF-κB, and Bcl-2 genes expression levels can effectively reflect malignant bone tumor growth of rabbit tibia. MDM2, NF-κB and Bcl-2 genes involved in primary bone tumors metastasis directly. It has important clinical significance for early diagnosis and treatment of primary bone tumor. 相似文献