Immunology report - synthèse en anglais

IMMUNOLOGY REPORT

NUCLEAR FACTOR KAPPA B(NF-KB)

PRESENTED TO DR. LAMA FAWAZ

BY

FATIMA MAHDI

MALAK TAHA

MELISSA HARMOUCHE

Table of Contents

NUCLEAR FACTOR KAPPA B(NF-KB) 1

DEFINITION OF NF-KB: 3

ACTIVATION OF NF-KB: 4

Signals induced by NF-KB: 8

1) pro-inflammatory cytokines: 8

a) Interleukin-1 (alpha, beta): 8

b) Interleukin-6: 10

c) TNF-α: Tumor necrosis factor α: 13

2) apoptosis regulators : Bcl-2 15

3) Interleukin -8: 15

REFERENCES 17

DEFINITION OF NF-KB:

NF-κB (Nuclear Factor-KappaB) is a heterodimeric protein composed of different combinations of members of the Rel family of transcription factors. The Rel/NF-kB family of transcription factors are involved mainly in stress-induced, immune, and inflammatory responses. In addition, these molecules play important roles during the developmentof certain hemopoietic cells, keratinocytes, and lymphoid organ structures. More recently, NF-κB family members have been implicated in neoplastic progression and the formation of neuronal synapses. NF-kB is also an important regulator in cell fate decisions, such as programmed cell death and proliferation control, and is critical in tumorigenesis.

NF-κB is composed of homo- and heterodimers of five members of the Rel family including NF-kB1(p50), NF-kB2 (p52), RelA (p65), RelB, and c-Rel (Rel). Hetero and Homo-dimerization of NF-kB proteins which exhibit differential binding specificities includes p50/RelA, p50/c-Rel, p52/c-Rel, p65/c-Rel, RelA/RelA, p50/p50, p52/p52, RelB/p50 and RelB/p52. All the Rel proteins contain a conserved N-terminal region, called the RHD (Rel Homology Domain). The N-terminal part of the RHD contains the DNA-binding domain, whereas the dimerization domain is located in the C-terminal region of the RHD. Close to the C-terminal end of the RHD lies the NLS (Nuclear Localization Signal), which is essential for the transport of active NF-B complexes into the nucleus. NF-kB1 and RelA were the first NF-κB proteins to be identified. Their N-terminal 300 AA revealed high similarity to the oncoprotein v-Rel, its cellular homologue c-Rel and the Drosophila protein Dorsal what resulted in the terms Rel proteins and RHD. The Rel/NF-κB proteins can be divided into two groups: Only RelA (p65), RelB and c-Rel (and Dorsal and Dif in Drosophila) contain potent TDs (Transactivation Domains) within sequences C-terminal to the RHD. The TDs consist of abundant serine, acidic and hydrophobic aminoacids that are essential for transactivation activity. In contrast, p50 and p52 do not possess TDs, and therefore cannot act as transcriptional activators by themselves. NF-κB1and NF-κB2 are produced as p105 and p100 precursors, respectively. The NF-κB1 p105 precursor appears to undergo constitutive processing by the cellular proteasome that removes the C-terminal I-kB-like portion to generate p50. NF-kB2 p100 precursor can be processed to remove the I-kB-like C-terminus, allowing the active p52 N-terminal half to function in transcriptional regulation. Homo- or heterodimers of p50 and p52 were even reported to repress KappaB site-dependent transcription, possibly by competing with other transcriptionally active dimers (e.g. p50/RelA) for DNA binding {1}

NF-kappa B, as the master switch, is the primary means by which inflammation is adjusted. Many different molecules interact with NF-kB – some stimulating it (increasing inflammation) and others inhibiting it (decreasing inflammation.) The balance between these positive (pro-inflammatory) and negative (anti-inflammatory) influences determines the extent of inflammation at any given time.

NF-kB is scientifically known as a transcription factor regulates how and when the information in certain human genes becomes translated into new protein molecules. Among those genes are those that promote inflammatory responses, many of which also promote cell growth, survival, and transformation into cancer. Many others genes that come under the control of NF-kB are pro-inflammatory genes, that is, their products are inflammatory cytokines such as interleukins, tumor necrosis factor it also triggers the transcription ofanti-apoptotis genes thus make negative feedback on apoptosis

In healthy people, NF-kB serves a vital function just by remaining inactive in the cell’s cytoplasm when it is activated it translocated into the nucleus .n normal cases when the inflammation stimulus goes away NF-kB is then translocated back to cytoplasm.

ACTIVATION OF NF-KB:

NF-κB dimers are sequestered in the cytosol of unstimulated cells via non-covalent interactions with a class of inhibitor proteins, called IkBs. To date seven IkBs have been identified: IkB-alpha, IkB-beta, IkB-gamma, IkB-epsilon, BCL3, p100 and p105. All known IkBs contain multiple copies of a 30-33 aa sequence, called ankyrin repeats which mediate the association between IkB and NF-κB dimers. The ankyrin repeats interact with a region in the RHD of the NF-κB proteins and by this mask their NLS and prevent nuclear translocation. Signals that induce NF-κB activity cause the phosphorylation of IkBs, their dissociation and subsequent degradation, thereby allowing activation of the NF-kB complex. Activated NF-kB complex translocates into the nucleus and binds DNA at kB-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine) and induce gene expression. The degradation of IkB proteins that permits NF-KappaB molecules to move into the nucleus is also carried out by the proteasome but only after prior phosphorylation of IkB by the IKK (IkB Kinase Complex). The IKK is composed of three subunits: two, IKK-alpha (IKK1) and IKK-beta (IKK2), are bonafide kinases, while the third, IKK-gamma (NEMO), has no catalytic activity but plays a critical regulatory role. IKK-alpha is the predominant

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