• Journal of Physiology & Pathology in Korean Medicine
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• v.21 no.4
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• pp.1017-1024
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• 2007

Thymus and activation-regulated chemokine (TARC/CCL-17), produced by keratinocytes, is a CC chemokine known to selectively Th2 type T cells via $CCR4^+$ and is implicated in the development of atopic dermatitis (AD). TARC/CCL17 expression was induced by cytokines such as tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and interferon-${\gamma}$ (IFN-${\gamma}$). We recently found that the wogonin, a flavone isolated from Scutellaria baicalensis, suppressed TARC expression via heme oxygenase 1 (HO1) in human keratinocytes induced with mite antigen. However, little is known about the inhibitory mechanism of wogonin on TARC/CCL-17 expression stimulated with cytokines. To investigate the inhibitory mechanism, I determined the inhibitory effects of wogonin on the activation of nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and $I{\kappa}B{\alpha}$ phosphorylation, and also examined the activation of p38 MAP kainase in HaCaT keratinocytes stimulated with TNF-${\alpha}$ and IFN-${\gamma}$. Wogonin inhibited NF-${\kappa}B$-DNA complex, NF-${\kappa}B$ binding activity, and the phosphorylation of $I{\kappa}B{\alpha}$ in a dose dependent manner. Wogonin also inhibited the translocation of NF-${\kappa}B$ from cytosol to nucleus. Moreover, the phosphorylation of of p38 MAP kinase in the TNF-${\alpha}$ and IFN-${\gamma}$-stimulated HaCaT keratinocytes were suppressed by wogonin in a dose dependent manner. These results suggest that wogonin may inhibit cytokine-induced NF-${\kappa}B$ activation by $I{\kappa}B{\alpha}$ degradation via suppression of p38 MAP kinase signaling pathway in keratinocytes and modulation of wogonin signaling pathway may be beneficial for the treatment of AD.

• Proceedings of the Korean Society of Toxicology Conference
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• 2001.05a
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• pp.144-144
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• 2001

Inappropriate up-regulation of cyclooxygenase-2 (COX-2) has been implicated for pathogenesis of various types of human cancer. COX-2 expression is known to be regulated by the eukaryotic transcription factor NF-$textsc{k}$B. In an attempt to link the NF-$textsc{k}$B activation and COX-2 induction, we have examined the kinetics of phorbol ester-induced activation of NF-$textsc{k}$B and COX-2 expression in the immortalized human breast epithelial cell line (MCF10A).(omitted)

• Journal of Acupuncture Research
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• v.22 no.2
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• pp.123-132
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• 2005

Melittin,cationic 26-amino acid, is the principal component of the bee venom (BV) which has been used for treatment of inflammatory disease such as arthritis rheumatism NF-kB is activated by subsequent release of inhibitory IkB via activation of a multisubunit IkB kinase (IKK). We previously found that melittin bind to the sulfhydryl group of p50, a subunit of NF-kB. Since sulfhydryl group is present in kinase domain of IKKa and IKKb, melittin could modify IKK activity by protein-protein interaction. We therefore examined effect of melittin on IKK activities in sodium nitroprusside (SNP)-stimulated synoviocyte obtained from RA patients. Melittin suppressed the SNP-induced release of IkB resulted in inhibition of DNA binding activity of NF-kB and NF-kB-dependent luciferase activity. Consistent with the inhibitory effect on NF-kB activation, IKKa and IKKb activities were also suppressed by melittin. Surface plasmon resonance analysis realized that melitin binds to IKKa $(Kd\;=\;1.34{\times}10-9M)$ and IKKb$(Kd\;=\;1.0{\times}10-9M)$. Inhibition of IKKa and IKKb resulted in reduction of the SNP-induced production of inflammatory mediators NO and PGE2 generation. The inhibitory effect of melittin on the IKKs activities, binding affinity of melittin to IKKs, and NO and PGE2 generation were blocked by addition of reducing agents dithiothreitol and glutathione. In addition, melittin did not show inhibitory effect in the transfected Synoviocytes with plasmid carrying dominant negative mutant IKKa (C178A) and IKKb (C179A). These results demonstrate that melittin directly binds to sulfhydryl group of IKKs resulting in IkBrelease, thereby inhibits activation of NF-kB and expression of genes involving in the inflammatory responses.

• BMB Reports
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• v.40 no.3
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• pp.341-348
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• 2007

Herpesvirus saimiri (HVS), a member of the $\delta$-herpesvirus family, encodes an oncoprotein called Saimiri Transforming Protein (STP) which is required for lymphoma induction in non-human primates. Previous study has shown that STP-C, an oncoprotein of HVS, activates NF-$\kappa$B signaling pathway. However, the detailed mechanism of STP-Cmediated NF-$\kappa$B activation has not been reported yet. We first report that STP-C interacts with TRAF6 protein in vivo and in vitro and further investigation shows that $Glu_{12}$ residue of STP-C is critical for binding to TRAF6. Introduction of ubiquitin together with STP-C augments NF-$\kappa$B activity compared to that of STP-C expression alone. STP-C expression further induces ubiquitination of endogenous TRAF6. In addition, either a deubiquitination enzyme, CYLD or a dominant negative E2-conjugation enzyme reduced NF-$\kappa$B activity in spite of the presence of STP-C, supporting that the interaction between STP-C and TRAF6 induces ubiquitination of TRAF6. NF-$\kappa$B activation by STP-C through the ubiquitinated TRAF6 causes the increased production of IL-8, an inflammatory chemokine and the enhanced expression of costimulatory molecule ICAM, which might ultimately contribute cellular transformation by the exposure of HVS-infected cells with inflammatory microenvironment and chronic activation.

• Journal of Microbiology and Biotechnology
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• v.17 no.8
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• pp.1338-1343
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• 2007

Angiogenesis is an essential step in tumor progress and metastasis. Accordingly, small molecules that inhibit angiogenesis would appear to be a promising way to cure angiogenesis-related diseases, including cancer. In the present study, we report that streptochlorin, a small molecule from marine actinomycete, exhibits a potent antiangiogenic activity. The compound potently inhibited endothelial cell invasion and tube formation stimulated with vascular endothelial cell growth factor (VEGF) at low micromolar concentrations where it showed no cytotoxicity to the cells. In addition, streptochlorin inhibited TNF-${\alpha}$-induced $NF-{\kappa}B$ activation in the newly developed cell-based reporter gene assay. These data demonstrate that streptochlorin is a new inhibitor of $NF-{\kappa}B$ activation and can be a basis for the development of novel anti-angiogenic agents.

• Archives of Pharmacal Research
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• v.27 no.10
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• pp.1073-1079
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• 2004

Interactions of the cell adhesion molecules are known to play important roles in mediating inflammation. The proinflammatory cytokine, tumor necrosis factor-${\alpha}$(TNF-${\alpha}$), activates the NF-kB signaling pathway, which induces the expression of various genes, such as intercellular adhesion molecule-1 (ICAM-1). In this study, the effect of vitamin C on the ICAM-1 expression induced by TNF-${\alpha}$ in a human neuroblastoma cell line, SK-N-SH was investigated. Treatment with vitamin C resulted in the downregulation of the TNF-${\alpha}$-induced surface expression and ICAM-1 mRNA levels in a concentration-dependent manner. Moreover, a gel shift analysis indicated that vitamin C dose-dependently inhibited the NF-kB activation and IkB${\alpha}$ degradation induced by TNF-${\alpha}$. Taken together, these results suggest that vitamin C downregulates TNF-${\alpha}$- induced ICAM-1 expression via the inhibition of NF-kB activation.

• BMB Reports
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• v.35 no.4
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• pp.371-376
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• 2002

The receptor activator of nuclear factor kappa B (RANK) is a member of the tumor necrosis factor (TNF) receptor superfamily. It plays a critical role in osteoclast differentiaion, lymph node organogenesis, and mammary gland development. The stimulation of RANK causes the activation of transcription factors NF-${\kappa}B$ and activator protein 1 (AP1), and the mitogen activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). In the signal transduction of RANK, the recruitment of the adaptor molecules, TNF receptor-associated factors (TRAFs), is and initial cytoplasmic event. Recently, the association of the MAPK kinase kinase, transforming growth factor-$\beta$-activated kinase 1 (TAK1), with TRAF6 was shown to mediate the IL-1 signaling to NF-${\kappa}B$ and JNK. We investigated whether or not TAK1 plays a role in RANK signaling. A dominant-negative form of TAK1 was discovered to abolish the RANK-induced activation of AP1 and JNK. The AP1 activation by TRAF2, TRAF5, and TRAF6 was also greatly suppressed by the dominant-negative TAK1. the inhibitory effect of the TAK1 mutant on RANK-and TRAF-induced NF-${\kappa}B$ activation was also observed, but less efficiently. Our findings indicate that TAK1 is involved in the MAPK cascade and NF-${\kappa}B$ pathway that is activated by RANK.

• Archives of Pharmacal Research
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• v.23 no.1
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• pp.54-58
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• 2000

To elucidate the molecular mechanisms for the suppression of LPS-induced nitric oxide (NO) production by a dehydrocostus lactone (DL) from Saussurea lappa, we examined the preventive effect of this compound on $NF-{\kappa}B$ activation in LPS-treated RAW 264.7 macrophages and U937 human monocytic cells. The results suggest that the suppression of NO production is mediated by the inhibitory action on the i-NOS gene expression through the inactivation of $NF-{\kappa}B$ and this sesquiterpene lactone can act as a pharmacological inhibitor of the $NF-{\kappa}B$ activation.

• BMB Reports
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• v.35 no.3
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• pp.337-342
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• 2002

Many components that are derived from medicinal or dietary plants possess potential chemopreventive properties. Curcumin, a yellow coloring agent from turmeric (Curcuma longa Linn, Zingiberaceae), possesses strong antimutagenic and anticarcinogenic activities. In this study, we have found that curcumin inhibits the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced nuclear factor ${\kappa}B$ (NF-${\kappa}B$) activation by preventing the degradation of the inhibitory protein $I{\kappa}B{\alpha}$ and the subsequent translocation of the p65 subunit in cultured human promyelocytic leukemia (HL-60) cells. Alternatively, curcumin repressed the TPA-induced activation of NF-${\kappa}B$ through direct interruption of the binding of NF-${\kappa}B$ to its consensus DNA sequences. Likewise, the TPA-induced DNA binding of the activator protein-1 (AP-1) was inhibited by curcumin pretreatment.

• Journal of Food Hygiene and Safety
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• v.25 no.3
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• pp.209-214
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• 2010

Metastasis is the primary cause of from breast cancer mortality. Cell migration and invasion play important roles in neoplastic metastasis. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix (ECM), plays an important role in cancer cell invasion. NF-${\kappa}B$ is transcription factor important in the regulation of MMP-9, as the promoter of MMP-9 gene contains binding sites for NF-${\kappa}B$. Brazilin, an active component of sappan wood (Caesalpinia sappan), decreases TPA-induced MMP-9 expression and invasion in MCF-7 cells. Also, brazilin suppressed NF-${\kappa}B$ activation in TPA-treated MCF-7 cells. Taken together, we demonstrated that the inhibition of TPA-induced MMP-9 expression and cell invasion by brazilin is mediated by the suppression of the NF-${\kappa}B$ pathway in MCF-7 cells. This result suggest brazilin provide a potential therapeutic app roach for the treatment of breast cancer.