Card9‐dependent IL‐1β regulates IL‐22 production from group 3 innate lymphoid cells and promotes colitis‐associated cancer |
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| Authors: | Hanna Bergmann Susanne Roth Konstanze Pechloff Elina A Kiss Sabine Kuhn Mathias Heikenwälder Andreas Diefenbach Florian R Greten Jürgen Ruland |
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| Institution: | 1. Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universit?t München, Munich, Germany;2. Chirurgische Klinik, Universit?tsklinikum Heidelberg, Ruprecht‐Karls‐Universit?t, Heidelberg, Germany;3. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany;4. Institut für Medizinische Mikrobiologie und Hygiene, Universit?tsmedizin Mainz, Mainz, Germany;5. Institut für Virologie, Technische Universit?t München/Helmholtz Zentrum München, Munich, Germany;6. Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany;7. Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany;8. German Center for Infection Research (DZIF), Munich, Germany |
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| Abstract: | Inflammatory bowel diseases (IBD) are key risk factors for the development of colorectal cancer, but the mechanisms that link intestinal inflammation with carcinogenesis are insufficiently understood. Card9 is a myeloid cell‐specific signaling protein that regulates inflammatory responses downstream of various pattern recognition receptors and which cooperates with the inflammasomes for IL‐1β production. Because polymorphisms in Card9 were recurrently associated with human IBD, we investigated the function of Card9 in a colitis‐associated cancer (CAC) model. Card9?/? mice develop smaller, less proliferative and less dysplastic tumors compared to their littermates and in the regenerating mucosa we detected dramatically impaired IL‐1β generation and defective IL‐1β controlled IL‐22 production from group 3 innate lymphoid cells. Consistent with the key role of immune‐derived IL‐22 in activating STAT3 signaling during normal and pathological intestinal epithelial cell (IEC) proliferation, Card9?/? mice also exhibit impaired tumor cell intrinsic STAT3 activation. Our results imply a Card9‐controlled, ILC3‐mediated mechanism regulating healthy and malignant IEC proliferation and demonstrates a role of Card9‐mediated innate immunity in inflammation‐associated carcinogenesis. |
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| Keywords: | Card9 Colitis‐associated‐cancer Innate lymphoid cells Interleukin‐1β Interleukin‐22 |
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