Inflammation-induced Occludin Downregulation Limits Epithelial Apoptosis by Suppressing Caspase-3 Expression.

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  • Additional Information
    • Source:
      Publisher: W.B. Saunders Country of Publication: United States NLM ID: 0374630 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0012 (Electronic) Linking ISSN: 00165085 NLM ISO Abbreviation: Gastroenterology Subsets: MEDLINE
    • Publication Information:
      Publication: Philadelphia, PA : W.B. Saunders
      Original Publication: Baltimore.
    • Subject Terms:
      Apoptosis*; Caspase 3/*metabolism ; Colitis/*enzymology ; Colon/*enzymology ; Epithelial Cells/*enzymology ; Intestinal Mucosa/*enzymology ; Occludin/*metabolism; Animals ; Caco-2 Cells ; Case-Control Studies ; Caspase 3/deficiency ; Caspase 3/genetics ; Colitis/chemically induced ; Colitis/genetics ; Colitis/pathology ; Colitis, Ulcerative/enzymology ; Colitis, Ulcerative/pathology ; Colon/pathology ; Crohn Disease/enzymology ; Crohn Disease/pathology ; Dextran Sulfate ; Disease Models, Animal ; Epithelial Cells/pathology ; Humans ; Intestinal Mucosa/pathology ; Mice, Inbred C57BL ; Mice, Knockout ; Occludin/deficiency ; Occludin/genetics ; Signal Transduction ; Trinitrobenzenesulfonic Acid ; Zonula Occludens-1 Protein/genetics ; Zonula Occludens-1 Protein/metabolism
    • Abstract:
      Background & Aims: Epithelial tight junctions are compromised in gastrointestinal disease. Processes that contribute to the resulting barrier loss include endocytic occludin removal from the tight junction and reduced occludin expression. Nevertheless, the relatively-normal basal phenotype of occludin knockout (KO) mice has been taken as evidence that occludin does not contribute to gastrointestinal barrier function. We asked whether stress could unmask occludin functions within intestinal epithelia.
      Methods: Wildtype (WT), universal and intestinal epithelial-specific occludin KO, and villin-EGFP-occludin transgenic mice as well as WT and occludin knockdown (KD) Caco-2 BBe cell monolayers were challenged with DSS, TNBS, staurosporine, 5-FU, or TNF. Occludin and caspase-3 expression were assessed in patient biopsies.
      Results: Intestinal epithelial occludin loss limited severity of DSS- and TNBS-induced colitis due to epithelial resistance to apoptosis; activation of both intrinsic and extrinsic apoptotic pathways was blocked in occludin KO epithelia. Promoter analysis revealed that occludin enhances CASP3 transcription and, conversely, that occludin downregulation reduces caspase-3 expression. Analysis of biopsies from Crohn's disease and ulcerative colitis patients and normal controls demonstrated that disease-associated occludin downregulation was accompanied by and correlated with reduced caspase-3 expression. In vitro, cytokine-induced occludin downregulation resulted in reduced caspase-3 expression and resistance to intrinsic and extrinsic pathway apoptosis, demonstrating an overall protective effect of inflammation-induced occludin loss.
      Conclusions: The tight junction protein occludin regulates apoptosis by enhancing caspase-3 transcription. These data suggest that reduced epithelial caspase-3 expression downstream of occludin downregulation is a previously-unappreciated anti-apoptotic process that contributes to mucosal homeostasis in inflammatory conditions.
      (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)
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    • Grant Information:
      R24 DK099803 United States DK NIDDK NIH HHS; K01 DK092381 United States DK NIDDK NIH HHS; R01 DK061931 United States DK NIDDK NIH HHS; P30 DK034854 United States DK NIDDK NIH HHS; R01 DK068271 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: Cell Death; Gene Regulation; IBD; Permeability
    • Accession Number:
      0 (OCLN protein, human)
      0 (Occludin)
      0 (Ocln protein, mouse)
      0 (Tjp1 protein, mouse)
      0 (Zonula Occludens-1 Protein)
      8T3HQG2ZC4 (Trinitrobenzenesulfonic Acid)
      9042-14-2 (Dextran Sulfate)
      EC 3.4.22.- (CASP3 protein, human)
      EC 3.4.22.- (Casp3 protein, mouse)
      EC 3.4.22.- (Caspase 3)
    • Publication Date:
      Date Created: 20190812 Date Completed: 20191219 Latest Revision: 20201101
    • Publication Date:
      20221213
    • Accession Number:
      PMC6815722
    • Accession Number:
      10.1053/j.gastro.2019.07.058
    • Accession Number:
      31401143