Nuclear-factor-K-B

Malignant Reed-Sternberg cells overexpress nuclear factor-K B, which is associated with cell proliferation and anti-apoptotic signals. Infections with viral and bacterial pathogens upregulate nuclear factor-K B. Epstein-Barr virus is found in many, but not all, HL tumors. 

Recent evidence suggests that atherosclerosis is a chronic inflammatory process. The recruitment of mononuclear leukocytes and formation of intimal macrophage-rich lesions at specific sites of the arterial tree are key events in atherogenesis. Alterations of chemotactic and adhesive properties of the endothelium play an important role in this process [82]. Quercetin has been reported to inhibit the expression in glomerular cells of monocyte chemoattractant protein-1 (MCP-1) [83] a potent chemoattractant for circulating monocytes. Red wine reduced MCP-1 mRNA and protein expression in abdominal aorta of cholesterol fed rabbits after balloon injury and this effect was associated with a reduced neointimal hyperplasia [84]. The antioxidant-mediated inhibition of nuclear factor k B (NFkB) and the subsequent non selective reduction of cytokine transcription have been suggested to be responsible for these effects [83]. Additionally, quercetin downregulated both phorbol 12-myristate 13-acetate (PMA)- and tumour necrosis factor-a (TNFa)-induced intercellular adhesion molecule-1 (ICAM-1) expression in human endothelial cells [86]. 

The downstream effectors of TRAF signaling are transcription factors in the nuclear factor k-B (NF-kB) and activator protein-1 (AP-1) family (Ghosh and Karin, 2002 Shaulian and Karin, 2002), which can turn on numerous genes involved in many aspects of cellular and immune functions. While the carboxyl terminal TRAF domain, containing a coiled-coil TRAF-N domain and a conserved TRAF-C domain, is both necessary and sufficient for TRAF self-association and receptor interaction, the amino terminal domain, containing RING and zinc-finger motifs, is important for downstream functions (Rothe et al, 1994). 

An alternative pathway involves the adaptor protein RAIDD (RIP-associated ICH/CED-3-homologous protein with a death domain), which is recruited by the Fas receptor via its C-terminal DD. At its N-terminus RAIDD contains a caspase recruitment domain (CARD) that is also present in procaspase-2. The adaptor protein TRADD (TNFR-associated death domain), most effectively bound following ligation of TNFR-1, functions as a platform that recruits several signalling molecules, such as TRAF-2 (the TNFR-associated factor-2), RIP (the receptor-interacting protein), both of which stimulate activation of NF-kB (the nuclear factor k B) and also FADD, which mediates activation of apoptosis (Ashkenazi and Dixit, 1998). TRAMP has been reported to bind TRADD, TRAF-2, FADD and caspase-8. TRAIL can bind either to a TRAIL-Rl trimer or to a TRAIL-R2 trimer, which recruit FADD and caspase-8 or caspase-10 (Schneider et al., 1997). 

Many inflammatory cytokines including IL-8 are regulated at transcriptional levels, and a variety of transcription factors such as nuclear factor-K B (NFkB) and activator protein-1 (AP-1) play important roles in such processes. Abe and coworkers [71] demonstrated that CAM repressed TNF-a-induced AP-1 activation in human bronchial epithelial cells. We studied the effect of EM and CAM on the phorbol myristate acetate (PMA)-induced activation of NFkB and AP-1. Pretreatment of EM and CAM before the PMA treatment showed an inhibitory effect on both of the transcription factors as assessed by electrophoretic mobility shift assay (EMSA) (Fig. 14) [20]. In contrast, the macrolides showed no effect on the activation of cyclic AMP-responsive element binding protein (CREB), suggesting that the suppressive effect on some transcription factors is specific. We further evaluated the effect of EM on the phosphorylation of inhibitor of NFkB (IkB), which is a crucial step for transactivation of NFkB. EM did not influence the phosphorylation processes in vitro (Okazaki et at, unpublished data, January 2001). These data suggest that EM acts at the process of nuclear translocation of... 

Brand K, Page S, Wall AK, Neumeier D, Baeuerle PA. Role of nuclear factor-K B in atherogenesis. Exp Physiol 1997 82 297-304. 

The activation of nuclear transcription factors has been shown to be necessary for the mechanism by which oxLDLs increase the expression of genes involved in the cell growth, differentiation, and prolifraative responses observed in atherosclerosis. In fact, it has been demonstrated that oxLDLs stimulate activator protein-1 (AP-1) DNA-binding activity in fibroblasts, SMCs, and ECs, possibly via JNKs and ERKs, and that lipid peroxidation products participates in this phenomenon. The stimulation of DNA-binding activity of another redox-sensitive transcription factor, nuclear factor k B (NF-kB), by oxLDL has also been described. ... 

Fuiia B, Deng L, Wu K, Baylor S, Kehn K, Li H, DonneUy R, Coleman T, Kashanchi F (2002) Enhancement of nuclear factor-kappa B acetylation by coactivator p300 and HIV-1 Tat proteins. J Biol Chem 277(7) 4973 980... 

Shimada, T., Waranabe, N., Ohtsuka, Y., Endoh, M., Kojima, K., Hiraishi, H., and Terano, A. (1999). Polaprezinc down-regulates proinflammatory cytokine-induced nuclear factor-kappa B activation and interleukin-8 expression in gastric epithelial cells. J. Pharmacol. Exp. Ther. 291, 345-352. 

Gupta S, Hastak K, Afaq F, Ahmad N, Mukhtar H. 2004. Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappa B and induction of apoptosis. Oncogene 23 2507-2522. 

Kim G. M., Xu J., Xu J. M., Song S. K., Yan P., Ku G., Xu X. M., and Hsu C. Y. (2001). Tumor necrosis factor receptor deletion reduces nuclear factor-kappa B activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. J. Neurosci. 21 6617-6625. 

Yi, A.K. and Krieg, A.M. (1998a) CpG DNA rescue from anti-IgM-induced WEHI-231 B lymphoma apoptosis via modulation of I kappa B alpha and I kappa B beta and sustained activation of nuclear factor-kappa B/c-Rel. J. Immunol., 160, 1240-1245. 

Ebadi, M., Sharma, S.K., Wanpen, S., and Amorpan, A., Coenzyme Q10 inhibits mitochondrial complex-1 down-regulation and nuclear factor-kappa B activation, J. Cell Mol. Med., 8, 213-222, 2004. 

Y3. Yamashita, N., Koizumi, H., Murata, M., Mano, K., and Ohta, K., Nuclear factor kappa B mediates interleukin-8 production in eosinophils. Int. Arch. Allergy Immunol. 120, 230—236 (1999). 

Ogata, N., Yamamoto, H., Kugiyama, K., Yasue, H., and Miyamoto, E. 2000. Involvement of protein kinase C in superoxide anion-induced activation of nuclear factor-kappa B in human endothelial cells. Cardiovasc Res 45 513-521. 

Haridas, V., Darnay, B. G., Natarajan, K., Heller, R., and Aggarwal, B. B. (1998). Overexpression of the p80 TNF receptor leads to TNF-dependent apoptosis, nuclear factor-kappa B activation, and c-Tun kinase activation. J. Immunol. 160, 3152-3162. 

Manna, S. K., Aggaewal, B. B. (1999). Immunosuppressive Leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. 

Schreck, R., Albermann, K. and Baeuerle, P.A. 1992. Nuclear factor kappa-B an oxidative stress-responsive transcription factor of eukaryotic cells. Free Rad. Res. Comm. 17 221-237. 

Chen, C.C., Wang, J.K., and Lin, S.B. (1998). Antisense oligonucleotides targeting protein kinase C-alpha, -beta I, or -delta but not -eta inhibit lipopolysaccharide-induced nitric oxide synthase expression in RAW 264.7 macrophages involvement of a nuclear factor kappa B-dependent mechanism. J Immunol 161, 6206-14. 

Desaki, M., Takizawa, H., Ohtoshi, T, Kasama, T., Kobayashi, K., Sunazuka, T, Omura, S., Yamamoto, K., and Ito, K. (2000). Erythromycin suppresses nuclear factor-kappa B and activator protein-1 activation in human bronchial epithelial cells. Biochem. Biophys. Res. Commun. 267, 124-128. 

Janssen, Y.M., Barchowsky, A., Treadwell, M., Driscoll, K.E., and Mossman, B.T., Asbestos induces nuclear factor kappa B (NF-kappa B) DNA-binding activity and NF-kappa B-dependent gene expression in tracheal epithelial cells, Proc, Natl. Acad. Sci. USA, 92, 8458-8462,1995. 

Pandey, M.K, B. Sung, AB. Kunnumakkara, et al. 2008. Berberine modifies cysteine 179 of I kappa B alpha kinase, suppresses nuclear factor-kappa B-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Res. 68 (13) 5370-5379. 

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