NF-KB in the physiology of the bone,

NF-KB family and regulationThe transcription factor NF-kB can be found in allcell types (Oeckinghaus, Ghosh, 2009). NF-KB family is involved in all cellreactions to stimuli, such as stress, cytokines, free radicals, ultravioletirradiation and attack from bacterial or bacterial antigens. Thus, they controla range of genes in response to changes in the environment.

NF-kB plays a key rolein regulating the immune response to infections and its dysfunctions have beenlinked to cancer (such as multiple myeloma), inflammatory processes, autoimmunediseases, septic shock, viral infections and diseases of the immune system (Oeckinghaus,Ghosh, 2009). NF-?Bis an important regulator of proinflammatory gene expression (Tak andFirestein, 2001). Transcription of proteins linked to the inflammatoryprocesses is controlled through NF-KB. Furthermore, this transcription factorhas a role in the physiology of the bone, skin, central nervous system andembryonic development, The NF-KBNF-kB is also considered to be involved insynaptic plasticity and memory processes. Since NF-KB family controls all theseprocesses, a dysregulation of NF-KB pathway can cause tremendous diseases, e.

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g.arthritis, immunodeficiency, autoimmunity or cancer. In mature B cells,macrophages, neurons and vascular smooth muscles, or in unhealthy cells liketumor cells, NF-KB is constitutive (Oeckinghaus, Ghosh, 2009).

Studies inknockout mice have shown that a dysfunction in the expression of RelA causesembryonic lethality and liver degeneration, while dysfunctions in p50 and RelBcause immunodeficiency, such as abnormal mitogen responses and antibodyproduction (Tak and Firestein, 2001). RelB is implicated in the development anddifferentiation of dendritic cells, and a mutation disrupting relB impairsantigen presentation.C-Rel and p52 have a role in the immune function. P50/p52 double knockout miceexhibit impaired development of osteoclasts and B cells. P50 homodimersactivate IL-1–induced collagenase expression in synoviocytes, binding to a criticalNF-?B–like binding site. Both p50 and p65 play a role in constitutive IL-6production in rheumatoid arthritis (RA) synovial fibroblasts, whereas p65activation by thrombin regulates ICAM-1 expression in endothelial cells.Heterodimers of p50 and p65 have a role in activation of inflammatory genes byIL-1 or TNF-? in human monocytes, and these effects are blocked by the anti-inflammatorycytokine IL-10 (Tak and Firestein, 2001).NF-kB activity is influenced at multiple levels andthe control activity of this transcription factor is highly regulated.

Post-translationalmodifications of various core components of this signaling pathway are involved (Oeckinghaus,Ghosh, 2009).  Five proteins compose theNF-KB family: p65 (RelA), RelB, c-Rel, p105/p50 (NF-KB1), and p100/52 (NF-KB2).These proteins associate each other forming homodimers or heterodimers and theRel homology domain, a shared 300 amino acid long domain, is required fordimerization, as well as DNA binding, nuclear translocation and interactionwith IkBs (inhibitor of NF-KB).

NF-KB regulates its regulators (IKBa, P105 ORa20) itself (Oeckinghaus, Ghosh, 2009). This generates in turn anauto-regulatory feedback loops. IkBs (IkBa, IkBb and IkB1, or p100 and p105)retain NF-kB in an inactive form in the cytosol in a dimeric form, so that theIkB proteins have a crucial role in signal responsiveness. Upon stimulation,BcI-3 and IkBz can be induced. These two proteins regulate the activity of thedimers of NF-Kb after the nuclear translocation. The IkB kinase complexphosphorylates IkB proteins degrade the inhibitors, and then NF-kB migrates tothe nucleus and the transcription of target genes is stimulated (Oeckinghaus,Ghosh, 2009).

I?Ba has a role in the transient activation of NF-kB, it works bindingthe p50-p65 heterodimer and the p50 homodimer, although it does not inhibit DNAbinding activity of the latter (Tak and Firestein, 2001). I?Bb has a role in thesustained activation. Itinhibits p50-p65 more strongly than it inhibits p50-RelB and p50-c-Relcomplexes, whereas I?Ba has similar effects on these complexes (Tak andFirestein, 2001). For the regulation of NF-KB, degradation of IkBs and nucleartranslocation are important steps, whereas it needs something more to elicite amaximal NF-kB response. Post-translational modifications such as phosphorylationby protein kinase A (PKA) is critical for p65 driven gene expression of manytarget genes (Oeckinghaus, Ghosh, 2009).

Synthesis of cytokines (e.g. TNF-?, IL-1?, IL-6, andIL-8), is mediated by NF-?B, as is the expression of cyclooxygenase 2 (Tak andFirestein, 2001). In patients with RA and osteoarthritis, IKK in primaryfibroblast-like synoviocytes isolated from synovium were studied. In thesecells, immunoreactive IKK protein is abundant and IKK-? and IKK-? areconstitutively expressed at the mRNA level.

IKK function in these cells can be greatly enhanced byTNF-? and IL-1, leading to degradation of endogenous I?B? and nucleartranslocation of NF-?B. Activation of this pathway and the consequent inductionof IL-6, IL-8, ICAM-1, and collagenase-1 expression depends specifically onIKK-?. Thus,transfection with adenoviral constructs encoding an IKK-? dominant-negativemutant prevents TNF?–mediated NF-?B nuclear translocation and proinflammatorygene expression in synoviocytes, whereas dominant-negative IKK-?mutant has noeffect (Tak and Firestein, 2001).

InflammationA coordinate activation of signaling pathwayscharacterise the inflammatory response. This turns in the regulation of theexpression of pro-inflammatory and anti-inflammatory mediators (Lawrence,2009). To activate NF-kB, phosphorylation, ubiquitination and proteolysis ofIkB are required (Oeckinghaus, Ghosh, 2009). Then, NF-kB is transferred to thenucleus and here it binds to specific sequences of the promoters. Cytokines areusually synthesised de novo and notstored (Blackwell and Christman, 1997). Thus, after an inflammatory stimulus,the cytokine genes are transcripted and NF-kB is crucial for this step sincethis transcription factor upregulates the transcription of a specific set ofcytokine genes.

Thereare many factors that determine the production of cytokine in response to aninflammation. According to Blackwell and Christman (1997), NF-kB has aninteraction with the glucocorticoid receptor. Moreover, rate ofposttranscriptional RNA processing, mRNA stability, and translation efficiencyhave a role in the network of cytokines. The p65 subunit of NF-kB and NF-IL6directly associate with each other and cooperatively transactivate IL-6 geneand IL-8 gene expression. Inflammation is usually associated with their coordinatedproduction and action, e.g. in the sepsis syndrome the bacterial endotoxin andother toxic products stimulate rapid production of TNF-a and IL-1b (Matsusaka etal.

, 1993). The p65 and p 50 homodimers, and the p50-p65heterodimers can recognise the motif GGGATTTCC of the IL-6 gene. IL-6 and IL-8are cytokines secreted by cells such as macrophages in response to other cytokinesafter an infection (Blackwell and Christman, 1997).

To activate the IL-6 gene,p50 and p65 need the presence of NF-IL6, otherwise the bond of the NF-KBsubunits with the gene is absent. An increase in the amount of p50 inhibits thecooperative effect of p65. Moreover, it acts with NF-IL6 to stimulate theexpression of IL-6, even though p65 is the most effective subunit (Matsusaka etal., 1993).

 The transcriptional activation of IL-8 and IL-6requires acooperative binding with the transcription factor NF–IL6 (Blackwell andChristman, 1997). Inaddition to the IL-6 gene,for regulation of many immune response and acute-phase response of the genesIL-8, TNF-a, IL-1,8, granulocyte colony stimulating factor, immunoglobulin Klight chain, and serum amyloid A-, the NF-KB binding sites are important (Matsusaka etal., 1993). The IL-6 production is constitutively activated by thetransactivator protein Tax of the human T-lymphotrophic leukemia virus 1. Theprotein Tax activates NF-KB that causes in part the constitutive production ofIL-6. Furthermore, this protein synergistically increases the activation of theIL-6 transcription by NF-IL6. In the study made by Matsusaka et al.

(1993) it was suggested thatthrough the protein Tax, the activation of these two factors can mediate theconstitutive expression of IL-6. Through the NF-kB and the NF-IL6 bindingsites, the transcription of the IL-8 gene is stimulated by the X product ofhepatitis B virus. The viral expression can be regulated by NF-IL6 and NF-KBthat bind the regulatory regions.

Furthermore, transcriptional factorscontrolling genes encoding inflammatory cytokines, including NF-KB and NF-IL6,are constitutively activated in other pathological conditions such asmalignancies and autoimmune diseases since constitutive expression of inflammatorycytokines are observed in these cases (Matsusaka et al., 1993).Chromatin and NF-kBinfluence each otherOne of the key regulatory mechanism is the dynamic alteration of the chromatinstate. The chromatin environment at stimulus-responsive NF-?B sites is a majordeterminant in transcription factor binding (Bhatt and Ghosh, 2014). Thechromatin state is also influenced by NF-kB through a variety of mechanisms.

The chromatin is recruited modifying co-activator complexes such as p300, thecompetitive eviction of negative chromatin modifications, and the recruitmentof components of the general transcriptional machinery. In their work, Bhattand Ghosh (2014) explain how the induction of the human interferon-b (IFNB)gene in response to viral infection is an example of transcription factorsynergy. The regulation of theIFN? enhanceosome is an example of transcriptional regulation through thecombinatorial control of multiple transcriptional factors. To summarise, three transcription factors (NF-kB, IRF3 / IRF7and ATF-2 / c-JUN) associate each other and allow the expression of this gene,which is dependent on the stimulus.

The first event is the binding of NF-kB tothe PRDII element stored in the promoter, which in turn facilitates the recruitmentof IRF and ATF-2 / c-Jun (Bhatt and Ghosh, 2014). These transcription factorsare assembled at the promoter and they have a role as a platform for thesequential recruitment of the PCAF chromatin modifying complex, the p300/CBPacetyltransferase, and subsequently the SWI/SNF chromatin remodeling complexes (Bhatt and Ghosh, 2014).  SWI/SNF remodels the downstream nucleosomethat encompasses the TATA box, thus allowing TBP binding and subsequentpre-initiation complex assembly. With the concerted work of these factors the presenceof a chromatin barrier can be resolved (Bhatt and Ghosh, 2014).

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