Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure

Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including...

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Bibliographic Details
Published in:	The Journal of clinical investigation Vol. 128; no. 11; pp. 5056 - 5072
Main Authors:	Armacki, Milena, Trugenberger, Anna Katharina, Ellwanger, Ann K, Eiseler, Tim, Schwerdt, Christiane, Bettac, Lucas, Langgartner, Dominik, Azoitei, Ninel, Halbgebauer, Rebecca, Groß, Rüdiger, Barth, Tabea, Lechel, André, Walter, Benjamin M, Kraus, Johann M, Wiegreffe, Christoph, Grimm, Johannes, Scheffold, Annika, Schneider, Marlon R, Peuker, Kenneth, Zeißig, Sebastian, Britsch, Stefan, Rose-John, Stefan, Vettorazzi, Sabine, Wolf, Eckhart, Tannapfel, Andrea, Steinestel, Konrad, Reber, Stefan O, Walther, Paul, Kestler, Hans A, Radermacher, Peter, Barth, Thomas Fe, Huber-Lang, Markus, Kleger, Alexander, Seufferlein, Thomas
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01-11-2018
Subjects:	Animal models Animals Apoptosis Biomedical research Colitis Cytokines Digestive system Disease Models, Animal Female Fetal Proteins - genetics Fetal Proteins - metabolism Gangrene Gastrointestinal diseases Gastrointestinal tract Immunomodulation Inflammation Inflammatory bowel disease Inflammatory bowel diseases Inflammatory Bowel Diseases - enzymology Inflammatory Bowel Diseases - etiology Inflammatory Bowel Diseases - genetics Inflammatory Bowel Diseases - pathology Inflammatory diseases Interleukin 6 Interleukin-6 - genetics Interleukin-6 - metabolism Intestine Intestines - enzymology Intestines - pathology Ischemia Kinases Large intestine Liver Mice Mucosa Multiple Organ Failure - enzymology Multiple Organ Failure - etiology Multiple Organ Failure - genetics Multiple Organ Failure - pathology Multiple Trauma - complications Multiple Trauma - enzymology Multiple Trauma - genetics Multiple Trauma - pathology Nuclear transport Permeability Phosphorylation Physiology Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism Rodents Sepsis Septic shock Stat3 protein STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Stem cells Swine Systemic inflammatory response syndrome Systemic Inflammatory Response Syndrome - enzymology Systemic Inflammatory Response Syndrome - etiology Systemic Inflammatory Response Syndrome - pathology Transcription Factor RelA - genetics Transcription Factor RelA - metabolism Trauma Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-α Tumors Vascular endothelial growth factor Inflammatory bowel disease Inflammation Tight junctions Gastroenterology Apoptosis
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Summary:	Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: AK and TS contributed equally to this work.
ISSN:	0021-9738 1558-8238
DOI:	10.1172/jci97912