NF-kB activation

There are several hundred reported NF-kB inhibitors (see www.nf-kb.org for a complete and updated list). These inhibitors include natural products, chemicals, metabolites, and synthetic compounds. A large majority of these products, in particular commonly used antiinflammatory drugs such as corticosteroids and the nonsteroidal antiinflammatory drugs (NSADDs) aspirin, sulindac, ibuprofen and sulphasalazine, have the ability to partially inhibit NF-kB activity in cell culture. However, the precise mechanism of action and the specific molecular targets of most of these inhibitors remain unclear. 

NF-kB Activators Proinflammatory cytokines Bacterial and viral infection Reactive oxygen species... 

Sustained NF-kB activation, TNF-a, IL-1, proliferation, signals (M-CSF, G-CSF), chemotaxis (MCP-1), adhesion (VCAM-1, ICAM-1), thrombogenesis (TF)... 

Fig. 2.2 Simplified scheme of oxidant/antioxidant regulation ofNF-KB activation. Different stimuli, leading to an increase of ROS generation inside the ceU, activate the phosphorylation of IkB inhibitory protein and the subsequent proteolysis. Thioredoxin (Trx) may reduce activated NF-kB proteins facilitating nuclear translocation.Qnce released from IkB, the NF-kB complex translocates into the nucleus and the binding to DNA domain in the promoters and enhancers of genes such as TNF-a, IL-1, proliferation and chemotactic factors, adhesion molecule. Some of these genes, in turn, may further induce NF-kB activation, leading to a vicious circle if the regulatory cellular system escapes from...

Table 2.1 Flavonoids and flavonoid-related compounds suppressing NF-kB activity in cell culture studies...

SUZUKI Y J, AGGARWAL B B and PACKER L (1992) alpha-Lipoic acid is a potent inhibitor of NF-kB activation in hnman T cells Biochemical Biophysical Research Communications 189, 1709-15. 

NF-KB-regulated gene products and TAKl-mediated NF-kB activation. Blood2007,109, 2727-2735. 

Aldieri E, Atragene D, Bergandi L, et al. Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-kB activation. FEBS Lett 2003 552(2—3) 141—144. 

Modulation of Nuclear Factor-Kappa B (NF-kB) Activation Pathway.466... 

SWNTs HiPCO HaCaT Oxidative stress (ROS production, NF-kB activation) [45]... 

Hamalainen M, Nieminen R, Vuorela P, Heinonen M and Moilanen E. 2007. Anti-inflammatory effects of flavonoids genistein, kaempferol, quercetin and daidzein inhibit STAT-1 and NF-kB activations whereas flavones, isorhamnetin, naringenins, and pelargonidin inhibit only NF-kB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophagues. Mediators Inflamm 2007 45673. 

Kim JH, Na HJ, Kim CK, Kim JY, Ha KS, Lee H, Chung HT, Kwon HJ, Kwon YG and Kim YM. 2008. The non-provitamin A carotenoid, lutein, inhibits NF-KB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-KB-inducing kinase pathways role of H2O2 in NF-kB activation. Free Radic Biol Med 45(6) 885-896. 

UV-irradiated cells. Using cell-free cytosolic keratinocyte extracts, Simon and colleagues26 confirmed the role of membrane oxidation in NF-kB activation. Particularly important aspects of the experimental design employed by Simon and colleagues was the use of keratinocytes versus cells derived from a cervical cancer patient, and the use of biologically relevant UVB (290 to 320 nm) radiation versus UVC (200 to 290 nm) radiation, which is filtered out by the atmospheric ozone layer and does not reach the earth s surface. Overall, these data indicate that the activation of cytokine transcription, a step essential for the induction of immune suppression, can occur independently of UV-induced DNA damage and suggest that membrane lipid oxidation can serve as a UV photoreceptor. 

Pestka, J. and Zhou H.R. Hck- and PKR-dependent mitogen-activated protein kinase phosphorylation and AP-1, C/EBP and NF-kB activation precedes deoxynivalenol-induced TNF-2 and MIP-2 expression. The Toxicologist 72, 121, 2003. 

The CSN3 subunit interacts with IKKy, a component of the IsrB-kinase complex controlling NF-kB activity [32]. Additionally, it is the binding site for the CSN-associated kinases CK2 and PKD [31]. The subunit of the translation-initiation factor 3 complex, Int6/eIF3e, and the ubiquitin-conjugating enzyme variant, COPIO, have been identified as other cellular interactors [33, 34]. Also the HIV-1 Tat protein interacts with CSN 3 (our unpublished data). 

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