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Regulation of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-??) in Inflammatory Bowel Diseases.

ABSTRACT: Inflammatory bowel diseases (IBD), encompassing both Crohn Disease (CD) and ulcerative colitis (UC) are globally prevalent diseases, impacting children of all ages. The hallmark of IBD is a perturbed immune system that leads to continuous inflammation in the gut and challenges optimal treatment. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-??), a nuclear transcription factor, plays a major role in gut homeostasis and contributes significantly toward a balanced, homeostatic immune system. Dysregulation in the NF-?? pathway and factors that regulate it lead to a state of uncontrolled inflammation and altered immunity, as typically observed in IBD. Levels of proinflammatory cytokines that are regulated through NF-?? are increased in both CD and UC. Genes known to activate NF-??, such as, Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Interleukin 23 (IL-23), are associated with IBD. Factors involved in inhibition of NF-??, such as A20 and TOLLIP, are also affected in IBD, resulting in failed inflammation suppression/regulation. NOD-2 and A20 have specifically been found to be strongly associated with pediatric IBD. Gut commensals are known to exert anti-inflammatory activities toward NF-?? and can have a potential role in attenuating inflammation that likely occurs due to microbial dysbiosis in IBD. Failure to terminate/downregulate NF-?? signaling results in chronic inflammation in IBD. Well-regulated control of inflammation in children with IBD can help better control the disease and suppress immune responses. Better understanding of factors that control NF-?? can potentially lead toward discovering targeted therapeutic interventions for IBD. Suppression of NF-?? can be achieved through many modalities including anti-sense oligonucleotides (ASOs), siRNA (small interfering RNA), factors regulating NF-??, and microbes. This review focuses on the role of NF-??, especially in pediatric IBD, and potential therapeutic venues for attenuating NF-??-induced inflammation.

SUBMITTER: Zaidi D

PROVIDER: S-EPMC6218406 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Regulation of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κβ) in Inflammatory Bowel Diseases.

Zaidi Deenaz D Wine Eytan E

Frontiers in pediatrics 20181030

Inflammatory bowel diseases (IBD), encompassing both Crohn Disease (CD) and ulcerative colitis (UC) are globally prevalent diseases, impacting children of all ages. The hallmark of IBD is a perturbed immune system that leads to continuous inflammation in the gut and challenges optimal treatment. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ), a nuclear transcription factor, plays a major role in gut homeostasis and contributes significantly toward a balanced, homeostatic ...[more]

PMID: 30425977

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Project description:OBJECTIVE:Although often studied independently, little is known about how aortic valve endothelial cells and valve interstitial cells interact collaborate to maintain tissue homeostasis or drive valve calcific pathogenesis. Inflammatory signaling is a recognized initiator of valve calcification, but the cell-type-specific downstream mechanisms have not been elucidated. In this study, we test how inflammatory signaling via NF?B (nuclear factor ?-light-chain enhancer of activated B cells) activity coordinates unique and shared mechanisms of valve endothelial cells and valve interstitial cells differentiation during calcific progression. Approach and Results: Activated NF?B was present throughout the calcific aortic valve disease (CAVD) process in both endothelial and interstitial cell populations in an established mouse model of hypercholesterolemia-induced CAVD and in human CAVD. NF?B activity induces endothelial to mesenchymal transformation in 3-dimensional cultured aortic valve endothelial cells and subsequent osteogenic calcification of transformed cells. Similarly, 3-dimensional cultured valve interstitial cells calcified via NF?B-mediated osteogenic differentiation. NF?B-mediated endothelial to mesenchymal transformation was directly demonstrated in vivo during CAVD via genetic lineage tracking. Genetic deletion of NF?B in either whole valves or valve endothelium only was sufficient to prevent valve-specific molecular and cellular mechanisms of CAVD in vivo despite the persistence of a CAVD inducing environment. CONCLUSIONS:Our results identify NF?B signaling as an essential molecular regulator for both valve endothelial and interstitial participation in CAVD pathogenesis. Direct demonstration of valve endothelial cell endothelial to mesenchymal transformation transmigration in vivo during CAVD highlights a new cellular population for further investigation in CAVD morbidity. The efficacy of valve-specific NF?B modulation in inhibiting hypercholesterolemic CAVD suggests potential benefits of multicell type integrated investigation for biological therapeutic development and evaluation for CAVD.

Project description:BackgroundExpression of kappa gene is under the control of distinct cis-regulatory elements, including the kappa intron enhancer (iE kappa) and the kappa 3' enhancer (3'E kappa). The active enhancers and expression of immunoglobulin is generally considered to be restricted to B lymphocytes. However, accumulating evidence indicated that epithelial cancer cells, including nasopharyngeal carcinoma (NPC) cell lines, express immunoglobulins. The mechanisms underlying the expression of Igs in nonlymphoid cells remain unknown. On the basis of our previous finding that expression of kappa light chain in NPC cells can be upregulated by EBV-encoded latent membrane protein 1(LMP1) through the activation of NF-kappaB and AP-1 signaling pathways, we thus use NPC cells as model to further explore the molecular mechanisms of nonlymphoid cells expressing Ig kappa.ResultsIn this study, luciferase reporter plasmid containing human wild-type iE kappa, and its derivative plasmids containing mutant binding sites for transcription factor NF-kappaB or AP-1 were constructed. Luciferase reporter assays demonstrate iE kappa is active in Ig kappa-expressing NPC cells and LMP1 expression can upregulate the activity of iE kappa in NPC cells. Mutation of the NF-kappaB or AP-1 site within and downstream the iE kappa, inhibition of the NF-kappaB and AP-1 pathways by their respective chemical inhibitor Bay11-7082 and SP600125 as well as stable or transient expression of dominant-negative mutant of I kappaB alpha (DNMI kappaB alpha) or of c-Jun (TAM67) indicate that both sites are functional and LMP1-enhanced iE kappa activity is partly regulated by these two sites. Gel shift assays show that LMP1 promotes NF-kappaB subunits p52 and p65 as well as AP-1 family members c-Jun and c-Fos binding to the kappa NF-kappaB and the kappa AP-1 motifs in vitro, respectively. Both chemical inhibitors and dominant negative mutants targeting for NF-kappaB and AP-1 pathways can attenuate the LMP1-enhanced bindings. Co-IP assays using nuclear extracts from HNE2-LMP1 cells reveal that p52 and p65, c-Jun and c-Fos proteins interact with each other at endogenous levels. ChIP assays further demonstrate p52 and p65 binding to the kappaB motif as well as c-Jun and c-Fos binding to the AP-1 motif of Ig kappa gene in vivo.ConclusionThese results suggest that human iE kappa is active in Ig kappa-expressing NPC cells and LMP1-stimulated NF-kappaB and AP-1 activation results in an augmenting activation of the iE kappa. LMP1 promotes the interactions of heterodimeric NF-kappaB (p52/p65) and heterodimeric AP-1 (c-Jun/c-Fos) transcription factors with the human iE kappa enhancer region are important for the upregulation of kappa light chain in LMP1-positive nasopharyngeal carcinoma cells.

Dataset Information

Regulation of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-??) in Inflammatory Bowel Diseases.

Publications

Regulation of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κβ) in Inflammatory Bowel Diseases.

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