Signaling pathway via TNF-α/NF-κB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis

Onizawa, Michio; Nagaishi, Takashi; Kanai, Takanori; Nagano, Kei; Oshima, Shigeru; Nemoto, Yasuhiro; Yoshioka, Atsushi; Totsuka, Teruji; Okamoto, Ryuichi; Nakamura, Toshio; Sakamoto, Naoya; Tsuchiya, Kiichiro; Aoki, Kazuhiro; Ohya, Keiichi; Yagita, Hideo; Watanabe, Mamoru

doi:10.1152/ajpgi.00071.2008

Cited by 153 publications

(147 citation statements)

References 53 publications

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“…Cytokines such as TNF-a or IL-6 have been deeply implicated in the development of CAC. TNF-a is a pro-inflammatory cytokine that activates the NF-jB pathway in IECs through its specific receptor [87]. IECspecific deletion of IKKb, a key molecule in the NF-jB pathway, reduced the incidence of colitis-induced tumorigenesis, suggesting that IEC-intrinsic NF-jB activation is a major regulator of CAC [88].…”

Section: Colitis-associated Cancer Represents Another Aspect Of Iec-dmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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Section: Colitis-associated Cancer Represents Another Aspect Of Iec-dmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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“…21,22 In the next set of experiments these triggers were used to assess the effects of TUDCA in vitro using the colonic HT29 and T84 cell lines. In colonocytes, bile acids are taken up by passive transport that may depend on the critical micellar concentration (B3 mM for TUDCA 23 ).…”

Section: Tudca Inhibits Receptor-mediated Apoptosis In Colonocytes Inmentioning

confidence: 99%

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Laukens

Devisscher

Bossche

et al. 2014

Laboratory Investigation

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Ulcerative colitis (UC) is characterized by increased epithelial cell death and subsequent breakdown of the intestinal epithelial barrier, which perpetuates chronic intestinal inflammation. Since fecal bile acid dysmetabolism is associated with UC and tauroursodeoxycholic acid (TUDCA) has been shown to improve murine colitis, we evaluated the effect of TUDCA on intestinal epithelial cell death in a mouse model of UC-like barrier dysfunction elicited by dextran sulfate sodium (DSS). We identified the prevention of colonic caspase-3 induction, a key proapoptotic marker which was also over-activated in UC, as the earliest event resulting in a clear clinical benefit. Whereas vehicle-treated mice showed a cumulative mortality of 40%, all TUDCA-treated mice survived the DSS experiment during a 14-day follow-up period. In line with a barrier protective effect, TUDCA decreased bacterial translocation to the spleen and stimulated mucin production. Similarly, TUDCA inhibited lipopolysaccharide-induced intestinal permeability and associated enterocyte apoptosis. The anti-apoptotic effect was confirmed in vitro by a dose-dependent inhibition of both receptor-dependent (using tumor necrosis factor and Fas ligand) and receptor-independent (staurosporine) caspase-3 induction in HT29 colonic epithelial cells. These data imply that caspase-3 activation is an early marker of colitis that is prevented by TUDCA treatment. These data, together with the previously reported beneficial effect in colitis, suggest that TUDCA could be an add-on strategy to current immunosuppressive treatment of UC patients.

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“…Paraffin-embedded sections (5 mm) were stained with H&E. The H&E-stained sections were analyzed without prior knowledge of the type of donors, recipients, and treatments. The degree of inflammation in the colon was graded according to a modification of the previously described scoring system (26,27). Briefly, for mucosal damage, 0 points were assigned to normal appearance, 1 point to discrete lymphoepithelial lesions, 2 points to diffuse crypt elongation, and 3 points to extensive crypt elongation or mucosal erosion/ulceration.…”

Section: Histopathological Examination Of Colitismentioning

confidence: 99%

The Development of Colitogenic CD4+ T Cells Is Regulated by IL-7 in Collaboration with NK Cell Function in a Murine Model of Colitis

Yamaji

Nagaishi

Totsuka

et al. 2012

The Journal of Immunology

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We previously reported that IL-7−/−RAG−/− mice receiving naive T cells failed to induce colitis. Such abrogation of colitis may be associated with not only incomplete T cell maintenance due to the lack of IL-7, but also with the induction of colitogenic CD4+ T cell apoptosis at an early stage of colitis development. Moreover, NK cells may be associated with the suppression of pathogenic T cells in vivo, and they may induce apoptosis of CD4+ T cells. To further investigate these roles of NK cells, RAG−/− and IL-7−/−RAG−/− mice that had received naive T cells were depleted of NK cells using anti-asialo GM1 and anti-NK1.1 Abs. NK cell depletion at an early stage, but not at a later stage during colitogenic effector memory T cell (TEM) development, resulted in exacerbated colitis in recipient mice even in the absence of IL-7. Increased CD44+CD62L− TEM and unique CD44−CD62L− T cell subsets were observed in the T cell-reconstituted RAG−/− recipients when NK cells were depleted, although Fas, DR5, and IL-7R expressions in this subset differed from those in the CD44+CD62L− TEM subset. NK cell characteristics were the same in the presence or absence of IL-7 in vitro and in vivo. These results suggest that NK cells suppress colitis severity in T cell-reconstituted RAG−/− and IL-7−/−RAG−/− recipient mice through targeting of colitogenic CD4+CD44+CD62L− TEM and, possibly, of the newly observed CD4+CD44−CD62L− subset present at the early stage of T cell development.

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Signaling pathway via TNF-α/NF-κB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis

Cited by 153 publications

References 53 publications

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

The Development of Colitogenic CD4+ T Cells Is Regulated by IL-7 in Collaboration with NK Cell Function in a Murine Model of Colitis

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