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Bergmann, H.* ; Roth, S.* ; Pechloff, K.* ; Kiss, E.A.* ; Kühn, S.* ; Heikenwälder, M. ; Diefenbach, A.* ; Greten, F.R.* ; Ruland, J.*

Card9-dependent IL-1β regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer.

Eur. J. Immunol. 47, 1342-1353 (2017)
Publ. Version/Full Text Research data DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Card9 ; Colitis-associated-cancer ; Innate Lymphoid Cells ; Interleukin-1β ; Interleukin-22; Inflammatory-bowel-disease; Hydrocarbon Receptor Ligands; Intestinal Epithelial-cells; Domain-containing Protein; Ulcerative-colitis; Susceptibility Loci; Crohns-disease; Mouse Model; Colon Carcinogenesis; T-cells
ISSN (print) / ISBN 0014-2980
e-ISSN 1521-4141
Quellenangaben Volume: 47, Issue: 8, Pages: 1342-1353 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken
Reviewing status Peer reviewed