1. Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure
- Author
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Anna Katharina Trugenberger, Thomas F. E. Barth, Tim Eiseler, Tabea Barth, Thomas Seufferlein, Eckhart Wolf, Benjamin M. Walter, Sebastian Zeißig, Ninel Azoitei, Paul Walther, Johannes Grimm, Alexander Kleger, Kenneth Peuker, Stefan O. Reber, Lucas Bettac, Markus Huber-Lang, Stefan Rose-John, Annika Scheffold, Stefan Britsch, Rebecca Halbgebauer, André Lechel, Johann M. Kraus, Peter Radermacher, Rüdiger Groß, Hans A. Kestler, Marlon R. Schneider, Christoph Wiegreffe, Konrad Steinestel, Sabine Vettorazzi, Christiane Schwerdt, Milena Armacki, Ann K. Ellwanger, Andrea Tannapfel, and Dominik Langgartner
- Subjects
Fetal Proteins ,STAT3 Transcription Factor ,0301 basic medicine ,Swine ,Multiple Organ Failure ,medicine.medical_treatment ,Inflammation ,Inflammatory bowel disease ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Intestinal mucosa ,medicine ,Animals ,Interleukin-6 ,Multiple Trauma ,Tumor Necrosis Factor-alpha ,business.industry ,Septic shock ,Kinase ,Transcription Factor RelA ,General Medicine ,Protein-Tyrosine Kinases ,Inflammatory Bowel Diseases ,medicine.disease ,Systemic Inflammatory Response Syndrome ,Intestines ,Systemic inflammatory response syndrome ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,Apoptosis ,030220 oncology & carcinogenesis ,Immunology ,Commentary ,Female ,medicine.symptom ,business - Abstract
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-alpha. A TNF-alpha 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.
- Published
- 2018
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