scholarly journals Colitis is associated with loss of LHPP and up-regulation of histidine phosphorylation in intestinal epithelial cells

2020 ◽  
Author(s):  
Markus Linder ◽  
Dritan Liko ◽  
Venkatesh Kancherla ◽  
Salvatore Piscuoglio ◽  
Michael N. Hall
Keyword(s):  
Epithelial Cells ◽  
Posttranslational Modification ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Channel Activity ◽  
Physiological Conditions ◽  
Inflammatory Bowel ◽  
Histidine Phosphorylation ◽  
Cycle Regulation

AbstractProtein histidine phosphorylation (pHis) is a posttranslational modification involved in cell cycle regulation, ion channel activity and phagocytosis (1). Using novel monoclonal antibodies to detect pHis (2), we recently reported that loss of the histidine phosphatase LHPP results in elevated pHis levels in hepatocellular carcinoma (3). Here, we show that intestinal inflammation correlates with loss of LHPP, in DSS-treated mice and in inflammatory bowel disease (IBD) patients. Increased histidine phosphorylation was observed in intestinal epithelial cells (IECs), as determined by pHis immunofluorescence staining of colon samples from a colitis mouse model. However, ablation of Lhpp did not cause increased pHis or promote intestinal inflammation in physiological conditions or after DSS treatment. Our observations suggest that increased histidine phosphorylation plays a role in colitis, but loss of LHPP is not sufficient to increase pHis or to cause inflammation in the intestine.

scholarly journals Temporal induction of intestinal epithelial hypoxia-inducible factor-2α is sufficient to drive colitis

2019 ◽  
Vol 317 (2) ◽  
pp. G98-G107 ◽  
Author(s):  
Sumeet Solanki ◽  
Samantha N. Devenport ◽  
Sadeesh K. Ramakrishnan ◽  
Yatrik M. Shah
Keyword(s):  
Inflammatory Bowel Disease ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Hypoxia Inducible Factor ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel

Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1α and HIF-2α (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1α decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2α exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2α in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2α led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear whether the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study used a mouse model to temporally modulate expression of intestinal epithelial HIF-2α to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2α in intestinal epithelial cells in adult mice increased expression of proinflammatory mediators; however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2α was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2α mediates inflammatory response and demonstrates that activation of HIF-2α is sufficient to exacerbate colitis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Hypoxia and activation of its downstream transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are notable features of IBD. HIF-1α has well-characterized protective roles in IBD; however, the role of HIF-2α has been less studied. Using novel HIF-2α mouse models, we show that activation of HIF-2α in intestinal epithelial cells is sufficient to exacerbate colitis.

scholarly journals Interleukin 34: a new modulator of human and experimental inflammatory bowel disease

2015 ◽  
Vol 129 (3) ◽  
pp. 281-290 ◽  
Author(s):  
Stephanie Zwicker ◽  
Gisele L. Martinez ◽  
Madeleen Bosma ◽  
Marco Gerling ◽  
Reuben Clark ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Epithelial Cells ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Macrophage Differentiation ◽  
Differentiation Factor ◽  
Experimental Inflammatory Bowel Disease ◽  
Inflammatory Bowel

The macrophage differentiation factor interleukin-34, produced by intestinal epithelial cells, is up-regulated in patients with inflammatory bowel disease, and may be a novel modulator of intestinal inflammation.

Proteomic response of inflammatory stimulated intestinal epithelial cells to in vitro digested plums and cabbages rich in carotenoids and polyphenols

2016 ◽  
Vol 7 (10) ◽  
pp. 4388-4399 ◽  
Author(s):  
Anouk Kaulmann ◽  
Sébastien Planchon ◽  
Jenny Renaut ◽  
Yves-Jacques Schneider ◽  
Lucien Hoffmann ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Bowel Diseases ◽  
Intestinal Epithelial Cells ◽  
Intestinal Cells ◽  
Intestinal Epithelial ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Proteomic Response

Proteomic response of intestinal cells as a model of inflammatory bowel diseases to digested plum and cabbage rich in polyphenols and carotenoids.

scholarly journals Unique Regulation of Enterocyte Brush Border Membrane Na-Glutamine and Na-Alanine Co-Transport by Peroxynitrite during Chronic Intestinal Inflammation

2019 ◽  
Vol 20 (6) ◽  
pp. 1504 ◽  
Author(s):  
Subha Arthur ◽  
Palanikumar Manoharan ◽  
Shanmuga Sundaram ◽  
M Rahman ◽  
Balasubramanian Palaniappan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Rabbit Model ◽  
Intestinal Epithelial ◽  
Mechanism Of Inhibition ◽  
Chronic Intestinal Inflammation

Na-amino acid co-transporters (NaAAcT) are uniquely affected in rabbit intestinal villus cell brush border membrane (BBM) during chronic intestinal inflammation. Specifically, Na-alanine co-transport (ASCT1) is inhibited secondary to a reduction in the affinity of the co-transporter for alanine, whereas Na-glutamine co-transport (B0AT1) is inhibited secondary to a reduction in BBM co-transporter numbers. During chronic intestinal inflammation, there is abundant production of the potent oxidant peroxynitrite (OONO). However, whether OONO mediates the unique alteration in NaAAcT in intestinal epithelial cells during chronic intestinal inflammation is unknown. In this study, ASCT1 and B0AT1 were inhibited by OONO in vitro. The mechanism of inhibition of ASCT1 by OONO was secondary to a reduction in the affinity of the co-transporter for alanine, and secondary to a reduction in the number of co-transporters for B0AT1, which were further confirmed by Western blot analyses. In conclusion, peroxynitrite inhibited both BBM ASCT1 and B0AT1 in intestinal epithelial cells but by different mechanisms. These alterations in the villus cells are similar to those seen in the rabbit model of chronic enteritis. Therefore, this study indicates that peroxynitrite may mediate the inhibition of ASCT1 and B0AT1 during inflammation, when OONO levels are known to be elevated in the mucosa.

7 LACTOBACILLUS REUTERI SUPPRESSES PRO-INFLAMMATORY DRIVEN REACTIVE OXYGEN SPECIES IN VITRO IN HUMAN INTESTINAL EPITHELIAL CELLS AND IN VIVO IN A TNBS COLITIS MOUSE MODEL

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S41-S41 ◽  
Author(s):  
Wenly Ruan ◽  
Melinda Engevik ◽  
Alexandra Chang-Graham ◽  
Joseph Hyser ◽  
James Versalovic
Keyword(s):  
Reactive Oxygen Species ◽  
Epithelial Cells ◽  
Lactobacillus Reuteri ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Oxygen Species ◽  
Intestinal Epithelial ◽  
Colitis Model

Abstract Background Reactive oxygen species (ROS) play a role in maintaining intestinal epithelial homeostasis and are normally kept at low levels via antioxidant compounds. Dysregulation of ROS can lead to intestinal inflammation and contribute to inflammatory bowel disease (IBD). Select gut microbes possess the enzymatic machinery to produce antioxidants whereas others can dysregulate levels of ROS. Our model microbe, Lactobacillus reuteri (ATCC PTA 6475), has been demonstrated to reduce intestinal inflammation in mice models. It contains the genes encoding two distinct GshA-like glutamylcysteine ligases. We hypothesize that L. reuteri can secrete γ-glutamylcysteine to suppress ROS, minimize NFκB activation and regulate secretion of e pithelial cytokines. Methods & Results Conditioned media from L. reuteri was analyzed via mass spectrometry to confirm the presence of γ-glutamylcysteine. All cysteine containing products including γ-glutamylcysteine were fluorescently tagged in the conditioned media and then incubated with HT29 cell monolayers as well as human jejunal enteroid (HJE) monolayers. γ-glutamylcysteine was demonstrated to enter intestinal epithelial cells based on microscopy. Next, a Thioltracker assay was used to show increased intracellular glutathione levels by L. reuteri secreted γ-glutamylcysteine. HT29 cells and HJEs were then treated with IL-1β or hydrogen peroxide, and L. reuteri metabolites as well as γ-glutamylcysteine significantly suppressed pro-inflammatory cytokine driven ROS and IL-8 production. L. reuteri secreted products also reduced activity of NFκB as determined by a luciferase reporter assay. γ-glutamylcysteine deficient mutants were generated by targeted mutagenesis of GshA genes, and these mutant L. reuteri strains had a diminished ability to suppress IL-8 production and ROS. To further test the role of L. reuteri secreted γ-glutamylcysteine in vivo, a 2,4,6-Trinitrobenzenesulfonic acid (TNBS)- induced mouse colitis model was used. Adolescent mice were orogavaged with PBS, L. reuteri, L. reuteri GshA2 mutant, or γ-glutamylcysteine for a week after which TNBS was rectally administered to induce colitis. We demonstrate that L. reuteri and γ-glutamylcysteine can suppress histologic inflammation compared to PBS control and L. reuteri GshA2 mutant groups. Conclusions Together these data indicate that L. reuteri secretes γ-glutamylcysteine which can enter the intestinal epithelial cells and modulate epithelial cytokine production. It acts via suppression of ROS and NFκB which then decreases IL-8 production. We are able to demonstrate this in vitro in both HT 29 cells and HJEs. We now also demonstrate this in vivo in a mouse colitis model. These experiments highlight a prominent role for ROS intermediates in microbiome-mammalian cell signaling processes involved in immune responses and intestinal inflammation.

OC.11.4 GATA6 DEFICIENCY IN THE INTESTINAL EPITHELIAL CELLS EXACERBATES INTESTINAL INFLAMMATION

2020 ◽  
Vol 52 ◽  
pp. S35-S36
Author(s):  
F. Laudisi ◽  
G. Bevivino ◽  
C. Stolfi ◽  
I. Marafini ◽  
E. Troncone ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial
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