Function and Activation of NF-kappaB in the Immune System

Abstract

NF-kappa B is a ubiquitous transcription factor. Nevertheless, its properties seem to be most extensively exploited in cells of the immune system. Among these properties are NF-kappa B's rapid posttranslational activation in response to many pathogenic signals, its direct participation in cytoplasmic/nuclear signaling, and its potency to activate transcription of a great variety of genes encoding immunologically relevant proteins. In vertebrates, five distinct DNA binding subunits are currently known which might extensively heterodimerize, thereby forming complexes with distinct transcriptional activity, DNA sequence specificity, and cell type- and cell stage-specific distribution. The activity of DNA binding NF-kappa B dimers is tightly controlled by accessory proteins called I kappa B subunits of which there are also five different species currently known in vertebrates. I kappa B proteins inhibit DNA binding and prevent nuclear uptake of NF-kappa B complexes. An exception is the Bcl-3 protein which in addition can function as a transcription activating subunit in th nucleus. Other I kappa B proteins are rather involved in terminating NF-kappa B's activity in the nucleus. The intracellular events that lead to the inactivation of I kappa B, i.e. the activation of NF-kappa B, are complex. They involve phosphorylation and proteolytic reactions and seem to be controlled by the cells' redox status. Interference with the activation or activity of NF-kappa B may be beneficial in suppressing toxic/septic shock, graft-vs-host reactions, acute inflammatory reactions, acute phase response, and radiation damage. The inhibition of NF-kappa B activation by antioxidants and specific protease inhibitors may provide a pharmacological basis for interfering with these acute processes.

Transfection of NFκB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts

“…1,39 Transcriptional activation of the genes encoding these adhesion molecules and cytokines is tightly regulated by a transcription factor, NFkB. 4,6,[9][10][11]13,40,41 Under normal conditions, NFkB is usually present with IkB in the cytosol as an inactive complex. However, when grafts are exposed to stimuli after transplantation such as ischemia/reperfusion injury, cells may be activated to promote IkB-phosphorylation, which induces NFkB to translocate to the nucleus and to bind to the promoter region of genes of several major inflammatory mediators, such as IL-1, iNOS, and TNF-a, and upregulate their transcription.…”

“…2,3 Nuclear factor kB (NFkB) is one of such transcription factors for genes whose products are critical for inflammation and immunity. 4 It rapidly translocates from the cytoplasm to the nucleus in response to a variety of extracellular signals and plays a pivotal role in the regulation of inflammatory changes by inducing coordinated transactivation of genes of major inflammatory mediators such as IL-1, IL-6, iNOS, and TNF-a [5][6][7][8][9][10][11] and adhesion molecules such as ICAM-1 and VCAM-1. [12][13][14] Cooper et al demonstrated a time-dependent increase in the DNA-binding activity of NFkB, which peaked at 3 days before rejection, in a rat cardiac allograft model.…”

Uncoupling protein-2: evidence for its function as a metabolic regulator

“…Oxidative bursts generating ROS also provide a defence against infectious agents [136]. At toxic concentrations, ROS are capable of damaging cellular membranes, proteins and DNA leading to eventual mitochondrial destruction and cellular apoptosis [123,127,128].…”

Identification of a tumor-associated mutant form of the NF-κB RelA gene with reduced DNA-binding and transactivating activities

“…In most cell types, NF-kB complexes (the prototype is the heterodimer p50/p65) are found in the cytoplasm as inactive forms, associated with a class of inhibitor proteins called IkBs. The activation of NF-kB may follow a wide variety of extracellular stimuli that lead to the phosphorylation, dissociation and subsequent degradation of IkB, thereby allowing NF-kB to be translocated to the nucleus where it can bind to speci®c cis-acting consensus sequences (kB sites) located in the promoters and enhancers of inducible genes (for reviews see Baeuerle and Henkel, 1994;Grilli et al, 1993;Siebenlist et al, 1994).…”

“…NFkB complexes are involved in the induction of gene encoding hematopoietic growth factors (e.g. IL-2, IL-6, G-CSF and GM-CSF), as well as growth control proteins (p53, c-myc, ras) (for review see Baeuerle and Henkel, 1994). Increased NF-kB activity occurs in response to a variety of growth stimuli, and this has been implicated in the proliferation of murine ®broblasts transformed by the p40Tax protein of human T-cell leukemia virus 1 (Kitajima et al, 1992).…”