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Original Article

Regulation of antiapoptotic and cytoprotective pathways in colonic epithelial cells in ulcerative colitis

Pages 1-29 | Accepted 25 Sep 2015, Published online: 29 Oct 2015
 

Abstract

Ulcerative colitis is an inflammatory bowel disease involving the colon resulting in bloody diarrhea and increased risk of colorectal cancer in certain patient subgroups. Increased apoptosis in the epithelial cell layer causes increased permeability, especially during flares; this leads to translocation of luminal pathogens resulting in a continued inflammatory drive. The present work investigates how epithelial apoptosis is regulated in ulcerative colitis. The main results are that Fas mediated apoptosis is inhibited during flares of ulcerative colitis, probably by an upregulation of cellular inhibitor of apoptosis protein 2 (cIAP2) and cellular FLICE-like inhibitory protein. cIAP2 is upregulated in regenerative epithelial cells both in ulcerative colitis and in experimental intestinal wounds. Inhibition of cIAP2 decreases wound healing in vitro possibly through inhibition of migration. Altogether, it is shown that epithelial cells in ulcerative colitis responds to the hostile microenvironment by activation of cytoprotective pathways that tend to counteract the cytotoxic effects of inflammation. However, the present studies also show that epithelial cells produce increased amounts of reactive oxygen species during stimulation with tumor necrosis factor-α and interferon-γ resulting in DNA instability. The combined effect of increased DNA-instability and decreased apoptosis responses could lead to neoplasia.

Acknowledgements

First, I would like to thank the patients willing to participate in scientific studies – not for the benefit for themselves but for the benefit of future patients. I would like to thank my mentor Professor Ole Haagen Nielsen for his ongoing support of my research from the beginning (as a medical student). Ole has consistently guided me and corrected my track when needed not only for the benefit of the scientific work but also for the forming of me as a physician and academician. I would also like to thank my colleagues at the Department of Gastroenterology, Medical Section, Herlev Hospital and especially my former chief Professor Jørgen Rask-Madsen for the ongoing support and willingness to provide laboratory facilities for my research. Without this support, I would not have been able to conduct the experimental work. I am especially thankful to my wife Claudia and my children Frida, Lisa and Villads for always supporting me and letting me persue my scientific interests with all that it takes – not the least in accepting countless hours of work after the clinical work had ended. I wish to thank all technicians and collaborators for support and contribution to my work.

Declaration of interest

The author report no conflicts of interest. The author alone is responsible for the content and writing of this article.

Notes

1B-lymphoma Mo-MLV insertion region 1 homologue (Bmi1) and other genes also have been identified as possible intestinal epithelial stem cell markers. Bmi1 is expressed in a cell population at the interface between the CBC cells and the TA cells, but the role of these cells and their interplay with the CBCs remain to be established.[Citation19,Citation20] Bmi1 is involved in self-renewal in haematopoietic cells and neural cells.[Citation21–23]

2Yet other forms of cell death have been proposed including accidental cell death and parthanatos.[Citation28]

3The BH123 proteins also can cause MOMP by interaction with other mitochondrial channel proteins such as the voltage-dependent anion channels (VDACs).[Citation41]

4It was later shown that loss of epithelial cell-cell contacts induces apoptosis.[Citation65]

5Since the introduction of the protocols for culture of primary stem cells, it has been possible to keep single cells alive.[13] Attempts to measure apoptosis by annexin V detection, however, has failed because nonapoptotic epithelial cells expose high levels of annexin V on the surfaces of their cell mebranes for unknown reasons (Toshiro Sato, personal communication). The PI-based method described here, therefore, is still the standard method for measuring apoptosis in primary intestinal epithelial cells.

6The originally used anibody (polyclonal rabbit antihuman cIAP2 antibodies; R&D Systems, Abingdon, UK) was discontinued by the company. An inquiry was made on the reason for this, which the company would not answer, but the company claimed that it was not due to problems with specificity of the antibody. In subsequent studies, a monoclonal rabbit antihuman cIAP2 antibody from Nordic BioSite AB, Taby, Sweden, was used. This antibody performed similar to the original antibody in immunoblotting and immunohistochemistry, although more epithelial cells were stained positive in active UC.

7In the “Methods” section of the paper, it is stated that cells were grown up to 9 weeks.[Citation126] In the “Results” section, it is stated that cells were grown for up to 11 weeks. The last figure is correct. Figure 2 shows photomicrographs of one representative study with H2-DCF incubation of HT29 cell cultures. Three experiments were performed, including all different stimulation regimes. This is why the results were not tested statistically. However, data pooled from nine experiments with long-term exposure of the cells to a combination of 100 pM TNF- and 10 pM IFN-γ compared with controls showed an increased number of fluorescent cells per power field (/F) compared with unstimulated cells [stimulated cells: median 13.00 cells/F, range 4–35 cells/F; unstimulated cells: 1 cell/F, 0–1 cell/F; p < 0.001 (Mann–Whitney test)].

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