NF-κB is a protein complex that controls the transcription of DNA know as transcription factor which in turn regulate the expression of various genes. NF-κB is found in almost all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and infectious antigens. NF-kB family of transcription factors are involved mainly in stress-induced, immune, and inflammatory responses. NF-κB plays a key role in regulating the immune response to infection. NF-kB can be activated by inflammatory cytokines such as TNF (Tumor Necrosis Factor) or IL-1 (Interleukin-1). The most potent NF-kB activators are the proinflammatory cytokines IL-1 and TN Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. Normally, NF-kB are present in cells in an inactive state. In unstimulated cells, the NF-κB are sequestered in the cytoplasm by a family of inhibitors, called IκBs (Inhibitor of κB), NF-kB is activated upon signal transduction pathways by various external stimuli signals. Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins. The activation of NF-kB triggers the transcription of DNA and gene expressions.

The most potent NF-kB activators are the proinflammatory cytokines IL-1 and TNF. The upstream and proximal kinases of NF-kB signal transduction pathway by TNF, IL-1, Toll, LPS, and CD28, has been clearly identified. MAPKKK families of kinases (MEKK1,NIK, Akt, MLK3,TAK1) mediate the NF-kB signaling pathways. They are the upstream kinase of IKK. IKK (IkB kinase complexes). IKK specifically, phosphorylates the inhibitory IκBα protein. This phosphorylation results in the dissociation of IκBα from NF-κB. NF-κB, which is now free migrates into the nucleus and activates the expression of at least 150 genes. The various stimuli that activate NF-kB cause phosphorylation of IkB, which is followed by its ubiquitination and subsequent degradation. Ubiquitin is a small regulatory protein that has been found in almost all tissues (ubiquitously) of eukaryotic organisms. Among other functions, it directs protein recycling. Ubiquitin can be attached to proteins and label them for destruction. The ubiquitin tag directs proteins to the proteasome, which is a large protein complex in the cell that degrades and recycles unneeded proteins.

There are two NF-kB cascade of activation signaling pathways known as the canonical (classical) pathway for NF-kB RelA, c-Rel, RelB and p50) and the non-canonical (alternative) pathway for p100/RelB complex. The common regulatory step in both of these cascades of pathways is the activation of IkB kinase (IKK) complex and the regulatory non-enzymatic scaffold protein NEMO (also known as IKKg). In the canonical signaling pathway, binding of ligand (stimuli) to a cell surface receptor leads to the recruitment of adaptors (such as TRAF) to the cytoplasmic domain of the receptor.

The non-canonical pathway is activated during the development of lymphoid organs responsible for the generation of B and T lymphocytes (Figure 2). Only a small number of stimuli are known to activate NFkB via this pathway and these factors include lymphotoxin B and B cell activating factor (BAFF). This pathway utilizes an IKK complex that comprises two IKKa subunits with not NEMO. In the non-canonical pathway, NFkB-inducing kinase (NIK) is activated, which phosphorylates and activates the IKKa complex.

NF-kB play important roles in inflammation. Using large-scale genomic microarray screens, it was determined that NF-kB was the transcription factor also most associated with aging, particularly inflammaging. Scientist identified NF-kB as a master regulator of aging-associated gene expression programs effectively demonstrating that an increase in NF-kB gene expression is a common theme of the epigenetic programming of the aging. A focused analyses of its role in inflammaging have revealed that NF-κB expression is regulated by FOXO transcription factors, which are also involved in longevity assurance. Ultraviolet (UV) is considered to be the major external cause of skin aging, termed as photoaging. It is well established that nuclear factor kappa B (NF-kappaB) is activated upon UV irradiation and induces various genes including interleukin-1 (IL-1), tumor necrosis factor alpha (TNFalpha), and matrix metalloprotease-1 (MMP-1). Elevated MMP level induced in chronic inflammation is directly responsible for the aging signs of skin including wrinkles fine lines, laxity (see post “Matrix Metalloproteinases (MMPs) And MMP Inhibitors In Wrinkle Creams”). It is found that either UVB, IL-1 or TNFalpha could induce NF-kappaB by activating its signal transduction pathway. It is also known that production of basic fibroblast growth factor (bFGF) is induced in skin tissues by UV irradiation and it promotes the proliferation of skin keratinocytes and melanocytes. Activated NF-kB produces MMP-1 and bFGF in skin fibroblasts and human keratinocyte cell line.

Studies found that parthenolide and magnolol, the NF-kappaB inhibitors, could block UVB-mediated skin changes. Either parthenolide or magnolol could effectively inhibit the gene expression mediated by NF-kB and the production of bFGF and MMP-1 from cells overexpressing p65, a major subunit of NF-kB. These NF-kB inhibitors could inhibit the UVB-induced proliferation of keratinocytes and melanocytes in in vivo experiments. These findings suggest that NF-kappaB inhibitors may be useful in preventing the skin photoaging. Other similar studies also showed that inhibiting NF-kB promoted younger looking skin.

Yet how much it is safe to inhibit NF-kB on the skin remains to be seen. Because NF-kB is the end of various signaling pathways, inhibition of NF-kB will block all NF-kB pathways via different core signaling cascades. Doctors warn that too much inhibition of NF-kB might cause too much rejuvenation and cell proliferation and may cause cancer. Indeed, NF-kB is produced naturally in response to numerous causes of stress, including UV irradiation, gamma-irradiation, topoisomerase poisons, and DNA-breaking, and it remains to be seen how much NF-kB inhibition preserves necessary immunological function in the skin or otherwise.

There is one thing scientists do know, and that is the fact that there are a number of known antioxidants and treatments able to inhibit NF-kB induction. A number of ingredients have been touted to have NF-kB inhibitory activities everything from alpha-lipoic acid to vitamin C to exercise. However, these antioxidants may not the direct inhibitors of NF-kB because ROS or free radical can also induce NF-kB signaling pathways. Inhibition of ROS can inhibit the ROS induced NF-kB pathway. While these treatments may not result in as optimized NF-kB inhibition many of which are available and believed to be safe.