The IL-22–oncostatin M axis promotes intestinal inflammation and tumorigenesis
Multicellular cytokine networks drive intestinal inflammation and colitis-associated cancer (CAC). Interleukin-22 (IL-22) exerts both protective and pathogenic effects in the intestine, but the mechanisms that regulate this balance remain unclear. Here, we identify that IL-22 directly induces responsiveness to the IL-6 family cytokine oncostatin M (OSM) in intestinal epithelial cells (IECs) by activating STAT3 and upregulating the OSM receptor. In turn, OSM synergizes with IL-22 to sustain STAT3 activation in IECs and promote proinflammatory epithelial adaptation and immune cell chemotaxis to the inflamed intestine. Conditional deletion of the OSM receptor in IECs protects mice from both colitis and CAC, and pharmacological blockade of OSM attenuates established CAC. Thus, IL-22 and OSM form a pathogenic circuit that drives inflammation and tumorigenesis. Our findings reveal a previously unknown mechanism by which OSM supports intestinal pathology and highlight the IL-22-OSM axis as a promising therapeutic target for inflammatory bowel disease and CAC.
Authors
- Béatrice Bréart
- Stefan Wirtz (ORCID: https://orcid.org/0000-0001-6936-7431)
- Luis Alberto Blázquez Hernando (ORCID: https://orcid.org/0000-0001-9424-3908)
- Rocío López-Posadas (ORCID: https://orcid.org/0000-0002-2398-5864)
- Andreas Radbruch (ORCID: https://orcid.org/0000-0001-5753-0000)
- Sebastian Schürmann (ORCID: https://orcid.org/0000-0001-6497-9754)
- Max Löhning (ORCID: https://orcid.org/0000-0001-6382-7281)
- James Ziai (ORCID: https://orcid.org/0000-0002-2617-2279)
- Kai Hildner (ORCID: https://orcid.org/0000-0001-5007-4874)
- Andreas Diefenbach (ORCID: https://orcid.org/0000-0002-9176-9530)
- Saskia Hainbuch
- Lorenz Gerbeth (ORCID: https://orcid.org/0000-0001-6638-1959)
- Nils Müller (ORCID: https://orcid.org/0000-0003-1559-7711)
- Christian Bojarski (ORCID: https://orcid.org/0000-0001-7533-672X)
- Antigoni Triantafyllopoulou (ORCID: https://orcid.org/0000-0003-0123-7117)
- Petra Bächer (ORCID: https://orcid.org/0000-0003-4264-6451)
- Mariia Saliutina
- Imke Atreya (ORCID: https://orcid.org/0000-0002-2708-9688)
- Carl Weidinger (ORCID: https://orcid.org/0000-0002-9948-0088)
- Maximilian J. Waldner (ORCID: https://orcid.org/0000-0002-5560-7665)
- Anja A. Kühl (ORCID: https://orcid.org/0000-0003-2293-5387)
- Alexis Scherl
- Britta Siegmund (ORCID: https://orcid.org/0000-0002-0055-958X)
- Markus F. Neurath (ORCID: https://orcid.org/0000-0003-4344-1474)
- Hyun‐Dong Chang (ORCID: https://orcid.org/0000-0002-7341-4533)
- Jay V. Patankar (ORCID: https://orcid.org/0000-0002-1884-7424)
- Magdalena Prüß (ORCID: https://orcid.org/0000-0002-4522-7482)
- Roodline Cineus (ORCID: https://orcid.org/0000-0003-4393-5757)
- Susanne M. Krug (ORCID: https://orcid.org/0000-0002-1293-2484)
- Pawel Durek (ORCID: https://orcid.org/0000-0002-6179-0670)
- Moritz Leppkes (ORCID: https://orcid.org/0000-0003-2311-090X)
- Ashley D. Sanders (ORCID: https://orcid.org/0000-0003-3945-0677)
- Sebastian Zundler (ORCID: https://orcid.org/0000-0003-0888-2784)
- Mir‐Farzin Mashreghi (ORCID: https://orcid.org/0000-0002-8015-6907)
- Juliette Roels (ORCID: https://orcid.org/0000-0001-7230-3690)
- Chiara Romagnani (ORCID: https://orcid.org/0000-0002-5167-7463)
- Jörg–Dieter Schulzke (ORCID: https://orcid.org/0000-0001-9947-5521)
- Alexander Scheffold (ORCID: https://orcid.org/0000-0002-0626-343X)
- Jeffrey Hung
- Ahmed N. Hegazy (ORCID: https://orcid.org/0000-0002-2946-8251)
- Nikolaus Deigendesch (ORCID: https://orcid.org/0000-0002-6036-3327)
- Caroline Bosch‐Voskens
- Mary Keir (ORCID: https://orcid.org/0000-0002-0637-4092)
- Frederik Heinrich (ORCID: https://orcid.org/0000-0001-6097-5422)
- Gino Kwon (ORCID: https://orcid.org/0000-0002-4269-6638)
- Francesca Ronchi (ORCID: https://orcid.org/0000-0002-2035-6528)
- Joanna E. Klementowicz (ORCID: https://orcid.org/0000-0003-3339-2963)
- Thomas Conrad (ORCID: https://orcid.org/0000-0001-5618-6295)
- Elena von Coburg (ORCID: https://orcid.org/0009-0001-8546-8854)
- Leif S. Ludwig (ORCID: https://orcid.org/0000-0002-2916-2164)
- Gabriela Maria Guerra (ORCID: https://orcid.org/0000-0002-9773-4929)
- Kristina Koop (ORCID: https://orcid.org/0000-0002-1672-7234)
- Subhakankha Manna (ORCID: https://orcid.org/0000-0003-2360-0618)
- Nathalie Britzen‐Laurent (ORCID: https://orcid.org/0000-0002-0494-7117)
- Michael Stürzl (ORCID: https://orcid.org/0000-0002-9276-2824)
- Zlatko Trajanoski (ORCID: https://orcid.org/0000-0002-0636-7351)
- Nathaniel R. West (ORCID: https://orcid.org/0000-0001-9991-0503)
- Michael Schümann (ORCID: https://orcid.org/0000-0001-6391-9979)
- C Cancino
- Lifen Wang (ORCID: https://orcid.org/0009-0009-0536-4333)
- Christoph S. N. Klose
- Allan Konopka
- Diana Bösel
- Aya Abdelrahman
- Clemens Neufert
- Yanjiang Luo (ORCID: https://orcid.org/0009-0003-0401-467X)
Institutions
- University of Bonn (DE)
- Innsbruck Medical University (AT)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Basel (CH)
- Universität Innsbruck (AT)
- Max Delbrück Center (DE)
- University Hospital of Basel (CH)
- Leibniz Association (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Humboldt-Universität zu Berlin (DE)
- German Center for Pediatric and Adolescent Rheumatology (DE)
- Gene Therapy Laboratory (FR)
- German Rheumatism Research Centre (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1038/s41590-025-02149-z
- Citations
- 20
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 20.91