Hundreds of genes have been shown to be transcriptionally regulated by NF-κB [7
]. These include genes encoding cytokines, chemokines, and immunoreceptors, as well as proteins involved in antigen presentation, cell adhesion, the acute phase and stress responses, growth factors and their receptors, early response genes, and other transcription factors (www.nf-kb.org
The majority of the genes under NF-κB transcriptional control are involved in immune signaling and inflammatory responses. Indeed, transcriptional control of cytokine expression by NF-κB is likely one of the most important factors when evaluating the role of NF-κB in pathologic states. Some of these cytokines include TNFα, IL-1α/β, IL-2, 3, 6, 12, GM-CSF, M-CSF, and G-CSF. NF-κB also regulates expression of chemokines (MCP-1, KC, MIP-1 and several CCLs) and adhesion molecules (ICAM-1, E-selectin, and VCAM-1), which allow for the recruitment and attachment of immune cells to sites of inflammation. Furthermore, NF-κB upregulates the expression of receptors (CD80/81, IL-2Rα chain, TLR-2) and proteins involved in antigen presentation (MHC class I and β2 microglobulin) on immune cells, allowing for proper innate and adaptive immune responses.
In addition to regulating immune response genes, NF-κB regulates several additional biologic processes. Interestingly, NF-κB transcriptionally regulates both pro-apoptotic (Bim, Bax, Fas and Fas-ligand, and caspase 11) and anti-apoptotic (XIAP, bcl-2, A1/bfl-1, and c-Flip) genes. NF-κB blocks apoptosis in a number of inflammatory cells including macrophages, DC, T-cells, B-cells, and neutrophils and is a pro-survival factor in several types of malignancies especially lymphomas. In contrast, the inflammatory response can induce apoptotic cell death. This inflammatory cell death response is initiated by the production of cell death receptors (Fas and FasL) and intracellular apoptosis inducing proteins. This apoptotic death is further assisted by activated immune cells, which secrete granzyme, perforin and nitric oxide, all apoptosis inducing factors, which are regulated by NF-κB.
Another category of NF-κB transcriptionally regulated genes includes growth factors such as nerve growth factor (NGF), vascular endothelial growth factor (VEGF), insulin-like growth factor binding protein (IGFBP), bone morphogenic protein (BMP), and fibroblast growth factor (FGF). Many of the receptors for these growth factors are involved in the expansion and maturation of varying cell types. Of note, many other pathways associated with aging phenotypes are also cellular growth and expansion mediators including insulin/IGF-1, mTOR, and SIRT and will be discussed in more detail below. Thus, the majority NF-κB controlled genes are considered cell stress responders and lead to inflammation, apoptosis, and cellular growth/expansion.