scholarly journals The Inflammatory Bowel Disease Drug Azathioprine Induces Autophagy via mTORC1 and the Unfolded Protein Response Sensor PERK

2019 ◽  
Vol 25 (9) ◽  
pp. 1481-1496 ◽  
Author(s):  
Kirsty M Hooper ◽  
Victor Casanova ◽  
Sadie Kemp ◽  
Katherine A Staines ◽  
Jack Satsangi ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Flow Cytometry ◽  
Unfolded Protein Response ◽  
Bowel Disease ◽  
Unfolded Protein ◽  
Drug Mechanism ◽  
Mtorc1 Signaling ◽  
Inflammatory Bowel ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Background Genetic studies have strongly linked autophagy to Crohn’s disease (CD), and stimulating autophagy in CD patients may be therapeutically beneficial. The aim of this study was to evaluate the effect of current inflammatory bowel disease (IBD) drugs on autophagy and investigate molecular mechanisms of action and functional outcomes in relation to this cellular process. Methods Autophagy marker LC3 was evaluated by confocal fluorescence microscopy and flow cytometry. Drug mechanism of action was investigated by polymerase chain reaction (PCR) array with changes in signaling pathways examined by immunoblot and quantitative reverse transcription PCR (RT-qPCR). Clearance of adherent-invasive Escherichia coli (AIEC) and levels of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) were evaluated by gentamicin protection assays and RT-qPCR, respectively. The marker LC3 was analyzed in peripheral blood mononuclear cells (PBMCs) from pediatric patients by flow cytometry. Results Azathioprine induces autophagy via mechanisms involving modulation of mechanistic target of rapamycin (mTORC1) signaling and stimulation of the unfolded protein response (UPR) sensor PERK. Induction of autophagy with azathioprine correlated with the enhanced clearance of AIEC and dampened AIEC-induced increases in TNFα. Azathioprine induced significant increase in autophagosome bound LC3-II in PBMC populations ex vivo, supporting in vitro findings. In patients, the CD-associated ATG16L1 T300A single-nucleotide polymorphism did not attenuate azathioprine induction of autophagy. Conclusions Modulation of autophagy via mTORC1 and the UPR may contribute to the therapeutic efficacy of azathioprine in IBD.

scholarly journals Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding

2011 ◽  
Vol 441 (1) ◽  
pp. 87-93 ◽  
Author(s):  
J. Jasper Deuring ◽  
Colin de Haar ◽  
Chantal L. Koelewijn ◽  
Ernst J. Kuipers ◽  
Maikel P. Peppelenbosch ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Unfolded Protein Response ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Healthy Individuals ◽  
Infectious Colitis ◽  
Unfolded Protein ◽  
Inflammatory Bowel ◽  
The Unfolded Protein Response ◽  
Protein Response

Xenotoxic damage in inflammatory diseases, including IBD (inflammatory bowel disease), is compounded by reduced activity of the xenobiotic transporter ABCG2 (ATP-binding-cassette G2) during the inflammatory state. An association between the activation of the unfolded protein response pathway and inflammation prompted us to investigate the possibility that reduced ABCG2 activity is causally linked to this response. To this end, we correlated expression of ABCG2 and the unfolded protein response marker GRP78 (glucose-regulated protein of 78 kDa) in colon biopsies from healthy individuals (n=9) and patients with inactive (n=67) or active (n=55) IBD, ischaemic colitis (n=10) or infectious colitis (n=14). In addition, tissue specimens throughout the small bowel from healthy individuals (n=27) and from patients with inactive (n=9) or active (n=25) Crohn's disease were co-stained for ABCG2 and GRP78. In all biopsies from patients with active inflammation, irrespective of the underlying disease, an absolute negative correlation was observed between epithelial ABCG2 expression and GRP78 expression, suggesting that inflammation-dependent activation of the unfolded protein response is responsible for suppression of ABCG2 function. The link between the unfolded protein response and functional ABCG2 expression was further corroborated by live imaging of ABCG2-expressing cells, which showed that various inflammatory mediators, including nitric oxide, activate the unfolded protein response and concomitantly reduce plasma membrane localization as well as transport function of ABCG2. Thus a novel mechanism for explaining xenobiotic stress during inflammation emerges in which intestinal inflammation activates the unfolded protein response, in turn abrogating defences against xenobiotic challenge by impairing ABCG2 expression and function.

Su1764 Dissecting the Role of Unfolded Protein Response Pathway in Inflammatory Bowel Disease: In Silico mRNA-miRNA Co-Expression Analysis

2013 ◽  
Vol 144 (5) ◽  
pp. S-470 ◽  
Author(s):  
Orazio Palmieri ◽  
Teresa M. Creanza ◽  
Giuseppe Corritore ◽  
Tiziana Latiano ◽  
Nello Buccianti ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Unfolded Protein Response ◽  
Expression Analysis ◽  
Bowel Disease ◽  
In Silico ◽  
Unfolded Protein ◽  
Inflammatory Bowel ◽  
Protein Response

scholarly journals The Role of Autophagy and Related MicroRNAs in Inflammatory Bowel Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Shiyuan Wang ◽  
Yan Huang ◽  
Cili Zhou ◽  
Huangan Wu ◽  
Jimeng Zhao ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Posttranscriptional Regulation ◽  
Endoplasmic Reticulum Stress Response ◽  
Intestinal Fibrosis ◽  
Unfolded Protein ◽  
Inflammatory Bowel ◽  
New Perspective ◽  
The Unfolded Protein Response ◽  
Protein Response

Accumulating evidence demonstrates that microRNA- (miR-) mediated posttranscriptional regulation plays an important role in autophagy in inflammatory bowel disease (IBD), a disease that is difficult to manage clinically because of the associated chronic recurrent nonspecific inflammation. Research indicates that microRNAs regulate autophagy via different pathways, playing an important role in the IBD process and providing a new perspective for IBD research. Related studies have shown that miR-142-3p, miR-320, miR-192, and miR-122 target NOD2, an IBD-relevant autophagy gene, to modulate autophagy in IBD. miR-142-3p, miR-93, miR-106B, miR-30C, miR-130a, miR-346, and miR-20a regulate autophagy by targeting ATG16L1 through several different pathways. miR-196 can downregulate IRGM and suppress autophagy by inhibiting the accumulation of LC3II. During the endoplasmic reticulum stress response, miR-665, miR-375, and miR-150 modulate autophagy by regulating the unfolded protein response, which may play an important role in IBD intestinal fibrosis. Regarding autophagy-related pathways, miR-146b, miR-221-5p, miR-132, miR-223, miR-155, and miR-21 regulate NF-κB or mTOR signaling to induce or inhibit autophagy in intestinal cells by releasing anti- or proinflammatory factors, respectively.

Impeded protein folding and function in active inflammatory bowel disease

2011 ◽  
Vol 39 (4) ◽  
pp. 1107-1111 ◽  
Author(s):  
J. Jasper Deuring ◽  
Maikel P. Peppelenbosch ◽  
Ernst J. Kuipers ◽  
C. Janneke van der Woude ◽  
Colin de Haar
Keyword(s):  
Inflammatory Bowel Disease ◽  
Protein Folding ◽  
Bowel Disease ◽  
Intestinal Epithelial ◽  
Unfolded Protein ◽  
Membrane Bound ◽  
Inflammatory Bowel ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protective Proteins

The intestinal tract is covered by a total of 300 square metres of IECs (intestinal epithelial cells) that covers the entire intestinal mucosa. For protection against luminal xenobiotics, pathogens and commensal microbes, these IECs are equipped with membrane-bound transporters as well as the ability to secrete specific protective proteins. In patients with active IBD (inflammatory bowel disease), the expression of these proteins, e.g. ABC (ATP-binding cassette) transporters such as ABCG2 (ABC transporter G2) and defensins, is decreased, thereby limiting the protection against various luminal threats. Correct ER (endoplasmic reticulum)-dependent protein folding is essential for the localization and function of secreted and membrane-bound proteins. Inflammatory triggers, such as cytokines and nitric oxide, can impede protein folding, which causes the accumulation of unfolded proteins inside the ER. As a result, the unfolded protein response is activated which can lead to a cellular process named ER stress. The protein folding impairment affects the function and localization of several proteins, including those involved in protection against xenobiotics. In the present review, we discuss the possible inflammatory pathways affecting protein folding and eventually leading to IEC malfunction in patients with active IBD.

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