The IL-22-oncostatin M axis promotes intestinal inflammation and tumorigenesis

Cineus R, Luo Y, Saliutina M, Manna S, Cancino CA, Velasco Blázquez L, Wang L, Bösel D, Abdelrahman A, Klementowicz JE, Scherl A, Hainbuch S, Bréart B, Kwon G, Konopka A, Guerra GM, von Coburg E, Gerbeth L, Roels J, Heinrich F, Müller N, Durek P, Deigendesch N, Ziai J, Hung J, Conrad T, Kühl AA, Wirtz S, Löhning M, Keir M, Diefenbach A, Mashreghi MF, Siegmund B, Schumann M, Romagnani C, West NR, Hegazy AN (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Immunology Nature Research

Book Volume: 26

Pages Range: 837-853

Journal Issue: 6

DOI: 10.1038/s41590-025-02149-z

Abstract

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 with CRIS profile

Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

Freie Universität Berlin DE Germany (DE) Genentech Inc. US United States (USA) (US) Deutsches Rheuma-Forschungszentrum (DRFZ) DE Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE)

How to cite

APA:

Cineus, R., Luo, Y., Saliutina, M., Manna, S., Cancino, C.A., Velasco Blázquez, L.,... Hegazy, A.N. (2025). The IL-22-oncostatin M axis promotes intestinal inflammation and tumorigenesis. Nature Immunology, 26(6), 837-853. https://doi.org/10.1038/s41590-025-02149-z

MLA:

Cineus, Roodline, et al. "The IL-22-oncostatin M axis promotes intestinal inflammation and tumorigenesis." Nature Immunology 26.6 (2025): 837-853.

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