scholarly journals RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis

2019 ◽  
Vol 116 (42) ◽  
pp. 21140-21149 ◽  
Author(s):  
Se Kyu Oh ◽  
Dongha Kim ◽  
Kyeongkyu Kim ◽  
Kyungjin Boo ◽  
Young Suk Yu ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Target Genes ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Nuclear Factor Κb ◽  
Orphan Receptor ◽  
Intestinal Epithelial ◽  
Creb Binding Protein ◽  
Intestinal Homeostasis

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific RORα-deficient (RORαΔIEC) mice and find that RORα is crucial for maintaining intestinal homeostasis by attenuating nuclear factor κB (NF-κB) transcriptional activity. RORαΔIEC mice exhibit excessive intestinal inflammation and highly activated inflammatory responses in the dextran sulfate sodium (DSS) mouse colitis model. Transcriptome analysis reveals that deletion of RORα leads to up-regulation of NF-κB target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of RORα and histone deacetylase 3 (HDAC3) on NF-κB target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomain-containing protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that RORα/HDAC3-mediated attenuation of NF-κB signaling controls the balance of inflammatory responses, and therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of chronic inflammatory diseases, including inflammatory bowel disease (IBD).

scholarly journals IL-1β and the Intestinal Epithelial Tight Junction Barrier

2021 ◽  
Vol 12 ◽  
Author(s):  
Lauren W. Kaminsky ◽  
Rana Al-Sadi ◽  
Thomas Y. Ma
Keyword(s):  
Tight Junction ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Gene Activation ◽  
Nuclear Factor Κb ◽  
Systemic Circulation ◽  
Intestinal Lumen ◽  
Intestinal Epithelial ◽  
Kinase Gene ◽  
Epithelial Tight Junction

The intestinal epithelial tight junction (TJ) barrier controls the paracellular permeation of contents from the intestinal lumen into the intestinal tissue and systemic circulation. A defective intestinal TJ barrier has been implicated as an important pathogenic factor in inflammatory diseases of the gut including Crohn’s disease, ulcerative colitis, necrotizing enterocolitis, and celiac disease. Previous studies have shown that pro-inflammatory cytokines, which are produced during intestinal inflammation, including interleukin-1β (IL-1β), tumor necrosis factor-α, and interferon-γ, have important intestinal TJ barrier-modulating actions. Recent studies have shown that the IL-1β-induced increase in intestinal TJ permeability is an important contributing factor of intestinal inflammation. The IL-1β-induced increase in intestinal TJ permeability is mediated by regulatory signaling pathways and activation of nuclear transcription factor nuclear factor-κB, myosin light chain kinase gene activation, and post-transcriptional occludin gene modulation by microRNA and contributes to the intestinal inflammatory process. In this review, the regulatory role of IL-1β on intestinal TJ barrier, the intracellular mechanisms that mediate the IL-1β modulation of intestinal TJ permeability, and the potential therapeutic targeting of the TJ barrier are discussed.

scholarly journals An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer

2010 ◽  
Vol 207 (8) ◽  
pp. 1573-1577 ◽  
Author(s):  
Mark Asquith ◽  
Fiona Powrie
Keyword(s):  
Intestinal Inflammation ◽  
Innate Immune ◽  
Intestinal Epithelial ◽  
Intestinal Homeostasis ◽  
Functional Roles ◽  
Innate Immune Signaling ◽  
Distinct Disease ◽  
Inflammatory Bowel ◽  
Immune Sensing ◽  
Chronic Intestinal Inflammation

Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses to the intestinal microbiota, and by chronic intestinal inflammation. Several recent studies demonstrate the importance of innate microbial recognition by immune and nonimmune cells in the gut. Paradoxically, either diminished or exacerbated innate immune signaling may trigger the breakdown of intestinal homeostasis, leading to IBD and colitis-associated cancer (CAC). This dichotomy may reflect divergent functional roles for immune sensing in intestinal epithelial cells and leukocytes, which may vary with distinct disease mechanisms.

Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine

2014 ◽  
Vol 307 (7) ◽  
pp. G689-G699 ◽  
Author(s):  
Duc Ninh Nguyen ◽  
Per T. Sangild ◽  
Mette V. Østergaard ◽  
Stine B. Bering ◽  
Dereck E. W. Chatterton
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Intestinal Inflammation ◽  
Preterm Neonates ◽  
Epithelial Cell Line ◽  
Intestinal Epithelial ◽  
Intestinal Homeostasis ◽  
Erk Activation ◽  
Transforming Growth Factor Β2 ◽  
And Migration

A balance between pro- and anti-inflammatory signals from milk and microbiota controls intestinal homeostasis just after birth, and an optimal balance is particularly important for preterm neonates that are sensitive to necrotizing enterocolitis (NEC). We suggest that the intestinal cytokine IL-8 plays an important role and hypothesize that transforming growth factor-β2 (TGF-β2) acts in synergy with bacterial lipopolysaccharide (LPS) to control IL-8 levels, thereby supporting intestinal homeostasis. Preterm pigs were fed colostrum (containing TGF-β2) or infant formula (IF) with or without antibiotics (COLOS, n = 27; ANTI, n = 11; IF, n = 40). Intestinal IL-8 levels and NEC incidence were much higher in IF than in COLOS and ANTI pigs ( P < 0.001), but IL-8 levels did not correlate with NEC severity. Intestinal TGF-β2 levels were high in COLOS but low in IF and ANTI pigs. Based on these observations, the interplay among IL-8, TGF-β2, and LPS was investigated in a porcine intestinal epithelial cell line. TGF-β2 attenuated LPS-induced IL-6, IL-1β, and TNF-α release by reducing early ERK activation, whereas IL-8 secretion was synergistically induced by LPS and TGF-β2 via NF-κB. The TGF-β2/LPS-induced IL-8 levels stimulated cell proliferation and migration following epithelial injury, without continuous NF-κB activation and cyclooxygenase-2 expression. We suggest that a combined TGF-β2-LPS induction of IL-8 stimulates epithelial repair just after birth when the intestine is first exposed to colonizing bacteria and TGF-β2-containing milk. Moderate IL-8 levels may act to control intestinal inflammation, whereas excessive IL-8 production may enhance the damaging proinflammatory cascade leading to NEC.

scholarly journals The phytonutrient cinnamaldehyde limits intestinal inflammation and enteric parasite infection

2021 ◽  
Author(s):  
Ling Zhu ◽  
Audrey I.S. Andersen-Civil ◽  
Laura J. Myhill ◽  
Stig M. Thamsborg ◽  
Witold Kot ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Metabolic Diseases ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Host Responses ◽  
Mucosal Inflammation ◽  
Enteric Infection ◽  
Intestinal Epithelial ◽  
Mesenteric Lymph Nodes

AbstractPhytonutrients such as cinnamaldehyde (CA) have been studied for their effects on metabolic diseases, but their influence on mucosal inflammation and immunity to enteric infection are not well documented. Here, we show that consumption of CA significantly down-regulates transcriptional pathways connected to inflammation in the small intestine of mice. During infection with the enteric helminth Heligomosomoides polygyrus, CA-treated mice displayed higher growth rates and less worms, concomitant with altered T-cell populations in mesenteric lymph nodes. Furthermore, infection-induced changes in gene pathways connected to cell cycle and mitotic activity were counteracted by CA. Mechanically, CA did not appear to exert activity through a prebiotic effect, as CA treatment did not significantly change the composition of the gut microbiota. Instead, in vitro experiments showed that CA directly induced xenobiotic metabolizing pathways in intestinal epithelial cells and suppressed endotoxin-induced inflammatory responses in macrophages. Thus, CA down-regulates inflammatory pathways in the intestinal mucosa and regulates host responses to enteric infection. These properties appear to be largely independent of the gut microbiota and instead connected to CA’s ability to induce antioxidant pathways in intestinal cells. Our results encourage further investigation into the use of CA and related phytonutrients as functional food components to promote intestinal health in humans and animals.

scholarly journals Antiulcer Activity of Steamed Ginger Extract against Ethanol/HCl-Induced Gastric Mucosal Injury in Rats

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4663
Author(s):  
Jun-Kyu Shin ◽  
Jae Hyeon Park ◽  
Kyeong Seok Kim ◽  
Tong Ho Kang ◽  
Hyung Sik Kim
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Folk Medicine ◽  
Nuclear Factor Κb ◽  
Gastric Ulcers ◽  
Antiulcer Activity ◽  
Ginger Extract ◽  
Nitrite Production ◽  
Pro Inflammatory Cytokines

Ginger (Zingiber officianale), the most widely consumed species, is traditionally used as a folk medicine to treat some inflammatory diseases in China and Korea. However, the functional activity of steamed ginger extract on gastric ulcers has not been previously explored. The present study aimed to investigate antiulcer activity of steamed ginger extract (GGE03) against ethanol (EtOH)/HCl-induced gastric ulcers in a rat model. GGE03 (100 mg/kg) was orally administered for 14 days to rats before oral intubation of an EtOH/HCl mixture to induce gastric damage. Pretreatment with GGE03 markedly protected the formation of microscopic pathological damage in the gastric mucosa. Further, administration of GGE03 significantly increased mucosal total nitrate/nitrite production in gastric tissues, and elevated total GSH content, catalase activity and superoxide dismutase (SOD) expression as well as decreasing lipid peroxidation and myeloperoxidase (MPO) activity. Underlying protective mechanisms were examined by assessing inflammation-related genes, including nuclear factor-κB (NF-κB), prostaglandin E2 (PGE2), and pro-inflammatory cytokines levels. GGE03 administration significantly reduced the expression of NF-κB and pro-inflammatory cytokines. Our findings suggest that GGE03 possesses antiulcer activity by attenuating oxidative stress and inflammatory responses.

scholarly journals Adipocyte Enhancer-binding Protein-1 Promotes Macrophage Inflammatory Responsiveness by Up-Regulating NF-κB via IκBα Negative Regulation

2007 ◽  
Vol 18 (3) ◽  
pp. 930-942 ◽  
Author(s):  
Amin Majdalawieh ◽  
Lei Zhang ◽  
Hyo-Sung Ro
Keyword(s):  
Protein Interaction ◽  
Target Genes ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Nuclear Factor Κb ◽  
Physical Interaction ◽  
Eukaryotic Transcription ◽  
Protein Protein Interaction ◽  
Proinflammatory Mediators ◽  
Inhibitory Function

Nuclear factor κB (NF-κB) subunits comprise a family of eukaryotic transcription factors that are critically involved in cell proliferation, inflammation, and apoptosis. Under basal conditions, NF-κB subunits are kept under inhibitory regulation by physical interaction with NF-κB inhibitors (IκB subunits) in the cytosol. Upon stimulation, IκB subunits become phosphorylated, ubiquitinated, and subsequently degraded, allowing NF-κB subunits to translocate to the nucleus and bind as dimers to κB responsive elements of target genes. Previously, we have shown that AEBP1 enhances macrophage inflammatory responsiveness by inducing the expression of various proinflammatory mediators. Herein, we provide evidence suggesting that AEBP1 manifests its proinflammatory function by up-regulating NF-κB activity via hampering IκBα, but not IκBβ, inhibitory function through protein–protein interaction mediated by the discoidin-like domain (DLD) of AEBP1. Such interaction renders IκBα susceptible to enhanced phosphorylation and degradation, subsequently leading to augmented NF-κB activity. Collectively, we propose a novel molecular mechanism whereby NF-κB activity is modulated by means of protein–protein interaction involving AEBP1 and IκBα. Moreover, our study provides a plausible mechanism explaining the differential regulatory functions exhibited by IκBα and IκBβ in various cell types. We speculate that AEBP1 may serve as a potential therapeutic target for the treatment of various chronic inflammatory diseases and cancer.

scholarly journals RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1733
Author(s):  
In Kyu Lee ◽  
Hyerin Song ◽  
Hyerim Kim ◽  
Ik Soo Kim ◽  
Na Ly Tran ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Cholesterol Homeostasis ◽  
Orphan Receptor ◽  
Cholesterol Sulfate ◽  
Colon Cancers ◽  
Target Promoters

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8+ T cells by attenuating NF-κB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8+ T cells. Transcript analysis reveals that the suppression of RORα leads to the upregulation of NF-κB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of RORα and histone deacetylase (HDAC) on NF-κB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that RORα/HDAC-mediated attenuation of NF-κB signaling controls the balance of cholesterol metabolism in CD8+ T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.

scholarly journals MiR-146a is over-expressed and controls IL-6 production in cystic fibrosis macrophages

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Francesco R. Luly ◽  
Manuella Lévêque ◽  
Valerio Licursi ◽  
Giuseppe Cimino ◽  
Corinne Martin-Chouly ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Inflammation ◽  
Bacterial Infections ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Inherited Disease ◽  
Bacterial Killing ◽  
Significant Enrichment ◽  
The Impact

Abstract Cystic fibrosis (CF) is an inherited disease that is characterised by susceptibility to bacterial infections and chronic lung inflammation. Recently, it was suggested that macrophages contribute to impaired host defence and excessive inflammatory responses in CF. Indeed, dysfunction attributed to CF macrophages includes decreased bacterial killing and exaggerated inflammatory responses. However, the mechanisms behind such defects have only been partially defined. MicroRNAs (miRNAs) have emerged as key regulators of several macrophage functions, including their activation, differentiation and polarisation. The goal of this study was to investigate whether miRNA dysregulation underlies the functional abnormalities of CF macrophages. MiRNA profiling of macrophages was performed, with 22 miRNAs identified as differentially expressed between CF and non-CF individuals. Among these, miR-146a was associated with significant enrichment of validated target genes involved in responses to microorganisms and inflammation. As miR-146a dysregulation has been reported in several human inflammatory diseases, we analysed the impact of increased miR-146a expression on inflammatory responses of CF macrophages. These data show that inhibition of miR-146a in lipopolysaccharide-stimulated CF macrophages results in increased interleukin-6 production, which suggests that miR-146a overexpression in CF is functional, to restrict inflammatory responses.

scholarly journals Flagellin-Dependent and -Independent Inflammatory Responses following Infection by Enteropathogenic Escherichia coli and Citrobacter rodentium

2008 ◽  
Vol 76 (4) ◽  
pp. 1410-1422 ◽  
Author(s):  
Mohammed A. Khan ◽  
Saeid Bouzari ◽  
Caixia Ma ◽  
Carrie M. Rosenberger ◽  
Kirk S. B. Bergstrom ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Epithelial Cells ◽  
Diarrheal Disease ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Intestinal Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Citrobacter Rodentium

ABSTRACT Enteropathogenic Escherichia coli (EPEC) and the murine pathogen Citrobacter rodentium belong to the attaching and effacing (A/E) family of bacterial pathogens. These noninvasive bacteria infect intestinal enterocytes using a type 3 secretion system (T3SS), leading to diarrheal disease and intestinal inflammation. While flagellin, the secreted product of the EPEC fliC gene, causes the release of interleukin 8 (IL-8) from epithelial cells, it is unclear whether A/E bacteria also trigger epithelial inflammatory responses that are FliC independent. The aims of this study were to characterize the FliC dependence or independence of epithelial inflammatory responses to direct infection by EPEC or C. rodentium. Following infection of Caco-2 intestinal epithelial cells by wild-type and ΔfliC EPEC, a rapid activation of several proinflammatory genes, including those encoding IL-8, monocyte chemoattractant protein 1, macrophage inflammatory protein 3α (MIP3α), and β-defensin 2, occurred in a FliC-dependent manner. These responses were accompanied by mitogen-activated protein kinase activation, as well as the Toll-like receptor 5 (TLR5)-dependent activation of NF-κB. At later infection time points, a subset of these proinflammatory genes (IL-8 and MIP3α) was also induced in cells infected with ΔfliC EPEC. The nonmotile A/E pathogen C. rodentium also triggered similar innate responses through a TLR5-independent but partially NF-κB-dependent mechanism. Moreover, the EPEC FliC-independent responses were increased in the absence of the locus of enterocyte effacement-encoded T3SS, suggesting that translocated bacterial effectors suppress rather than cause the FliC-independent inflammatory response. Thus, we demonstrate that infection of intestinal epithelial cells by A/E pathogens can trigger an array of proinflammatory responses from epithelial cells through both FliC-dependent and -independent pathways, expanding our understanding of the innate epithelial response to infection by these pathogens.

scholarly journals Intestinal epithelial CD98 synthesis specifically modulates expression of colonic microRNAs during colitis

2012 ◽  
Vol 302 (11) ◽  
pp. G1282-G1291 ◽  
Author(s):  
Moiz A. Charania ◽  
Saravanan Ayyadurai ◽  
Sarah A. Ingersoll ◽  
Bo Xiao ◽  
Emilie Viennois ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Mirna Expression ◽  
Target Genes ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Small Noncoding Rnas

The transmembrane glycoprotein CD98 is known to be involved in intestinal inflammation. In the present study, we found that CD98 overexpression in intestinal epithelial cells does not normally affect the expression of colonic (epithelial and immune cell) microRNAs (miRNAs), small noncoding RNAs that posttranscriptionally regulate a wide variety of biological processes. However, upon dextran sulfate sodium (DSS) treatment, the expression of several colonic miRNAs, but not miRNAs from other tissues such as liver and spleen, were differentially regulated in mice overexpressing CD98 in epithelial cells compared with wild-type (WT) animals. For example, the level of colonic miRNA 132 was not affected by DSS treatment in WT animals but was upregulated in mice overexpressing CD98 in intestinal epithelial cells. Other colonic miRNAs, including colonic miRNA 23a and 23b, were downregulated in WT animals after DSS treatment but not in colonic epithelial cell CD98-overexpressing mice. Interestingly, the expression of potential miRNA target genes affected intestinal epithelial cells that overexpress CD98 and cell types that did not overexpress CD98 but were in close proximity to CD98-overexpressing intestinal epithelial cells. Taken together, these observations show that the combination of an inflammatory context and intestinal epithelial cell expression of CD98 affects the regulation of miRNA expression in colonic epithelial and immune cells. This is new evidence that protein expression modulates miRNA expression and suggests the existence of regulatory crosstalk between proteins and miRNAs in diseases such as colitis.

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