NF-??B Activation and Inhibition: A Review

Abstract

Among transcriptional regulatory proteins described, NF-kappaB seems particularly important in modulating the expression of immunoregulatory genes relevant in critical illness, inflammatory diseases, apoptosis, and cancer. In particular, NF-kappaB plays a central role in regulating the transcription of cytokines, adhesion molecules, and other mediators. The biochemical basis by which diverse stimuli converge to activate or intervene this family of transcription factors is still largely unknown. The NF-kappaB transcription factor family represents an important group of regulators of a broad range of genes involved in cellular responses to inflammatory and other kinds of signals. Knockout mouse studies have also revealed a key role for this family in broad physiological processes, including immune function and metabolism. Overall, specificity seems to exist in the role of each transcriptional complex in gene transcription and physiological function. Each NF-kappaB complex displays distinct affinities for the different DNA-binding sites present in the promoters of NF-kappaB-regulated genes, and this may contribute to some of the specificity exhibited. The identification of specific components of the NF-kappaB signal transduction pathway provides an opportunity to define mechanisms at the biochemical level by which specific members of the NF-kappaB family are activated. Furthermore, this may identify specific targets for selective inhibition or promotion of NF-kappaB functions. Further studies will be required to elucidate mechanisms regulating specificity and selectivity of NF-kappaB function, as well as its role in different diseases, prior to potential clinical application.

High glucose stimulates TNFα and MCP-1 expression in rat microglia via ROS and NF-κB pathways

“…NF-κB plays a key role in high glucose-induced TNFα and MCP-1 secretion from rat microglia NF-κB is one of the most important transcription factors in the expression of inflammatory genes [20] and is associated with the gene expression of TNFα and MCP-1 [20,21] . High glucose incubation has been shown to significantly enhance NF-κB activation by increasing its DNA binding activity [16] .…”

“…To detect the involvement of ROS in the TNFα and MCP-1 secretion induced by high glucose, we tested the effect of a nonspecific ROS scavenger, NAC. Microglia were pretreated with 2 mmol/L NAC for 60 min and then exposed to high glucose treatment for 24 h. NAC significantly prevented the high glucose-induced secretion of TNFα and MCP-1 ( Figure 3B, 3C), but NAC alone had no effect on TNFα and MCP-1 secretion.NF-κB plays a key role in high glucose-induced TNFα and MCP-1 secretion from rat microglia NF-κB is one of the most important transcription factors in the expression of inflammatory genes [20] and is associated with the gene expression of TNFα and MCP-1 [20,21] . High glucose incubation has been shown to significantly enhance NF-κB activation by increasing its DNA binding activity [16] .…”

The inhibition of TNF-α-induced NF-κB activation by marine natural products

“…This leads to the ubiquitination of the receptor-interacting protein (RIP) and to the activation of the transforming growth factor  (TGF-activated kinase 1 (TAK1) and of the IB kinase complex IKK (kinase of IB). Upon phosphorylation by IKK, IB is rapidly degraded and NF-B is released to translocate to the nucleus, where it binds to its target DNA sequences to initiate gene transcription [1,3,4,8,[15][16][17][18][19].…”

Protein Kinase A-Induced Phosphorylation of the p65 Subunit of Nuclear Factor-κB Promotes Schwann Cell Differentiation into a Myelinating Phenotype

“…Inhibition of NF-B or deletion of the p65 gene blocked the formation of myelin in Schwann cell-DRG neuron cocultures (Nickols et al, 2003). In unstimulated cells, NF-B is sequestered in the cytoplasm through the interaction with an inhibitory protein, nuclear factor B inhibitor (IB), which is phosphorylated and degraded after a variety extracellular stimuli such as cytokines, growth factors, and bacterial/viral infection (Sun and Andersson, 2002;Hoffmann et al, 2006;Perkins and Gilmore, 2006). Release from IB unmasks the nuclear localization signal of NF-B, which directs it to the nucleus in which NF-B-dependent gene transcription occurs.…”