Abstract
Cellular inhibitors of apoptosis proteins (cIAPs) are critical arbiters of cell death and key mediators of inflammation and innate immunity. cIAP2 is frequently overexpressed in colorectal cancer and in regenerating crypts of ulcerative colitis patients. However, its corresponding functions in intestinal homeostasis and underlying mechanisms in disease pathogenesis are poorly understood. We found that mice deficient in cIAP2 exhibited reduced colitis-associated colorectal cancer tumor burden but, surprisingly, enhanced susceptibility to acute and chronic colitis. The exacerbated colitis phenotype of cIAP2-deficient mice was mediated by increased cell death and impaired activation of the regenerative inflammasome-interleukin-18 (IL-18) pathway required for tissue repair following injury. Accordingly, administration of recombinant IL-18 or pharmacological inhibition of caspases or the kinase RIPK1 protected cIAP2-deficient mice from colitis and restored intestinal epithelial barrier architecture. Thus, cIAP2 orchestrates intestinal homeostasis by exerting a dual function in suppressing cell death and promoting intestinal epithelial cell proliferation and crypt regeneration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Azoxymethane
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Baculoviral IAP Repeat-Containing 3 Protein
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Cell Death / immunology
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Cell Survival / immunology
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Colitis / chemically induced
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Colitis / genetics
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Colitis / immunology*
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Colitis / pathology
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Colon / immunology
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Colon / pathology
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Colorectal Neoplasms / chemically induced
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / immunology*
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Colorectal Neoplasms / pathology
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Gene Expression Regulation
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Humans
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Inflammasomes / genetics
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Inflammasomes / immunology
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Inhibitor of Apoptosis Proteins / deficiency
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / immunology*
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Interleukin-18 / genetics
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Interleukin-18 / immunology
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Male
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Mice
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Mice, Knockout
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Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
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Signal Transduction
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Sodium Dodecyl Sulfate
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / immunology*
Substances
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Inflammasomes
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Inhibitor of Apoptosis Proteins
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Interleukin-18
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Sodium Dodecyl Sulfate
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Baculoviral IAP Repeat-Containing 3 Protein
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Birc3 protein, mouse
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Ubiquitin-Protein Ligases
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk1 protein, mouse
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Azoxymethane