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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月30日

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  • Roodline Cineus,
  • Yanjiang Luo,
  • Mariia Saliutina,
  • Subhakankha Manna,
  • Camila A. Cancino,
  • Luis Velasco Blázquez,
  • Lifen Wang,
  • Diana Bösel,
  • Aya Abdelrahman,
  • Joanna E. Klementowicz,
  • Alexis Scherl,
  • Saskia Hainbuch,
  • Béatrice Bréart,
  • Gino Kwon,
  • Agata Konopka,
  • Gabriela M. Guerra,
  • Elena von Coburg,
  • Lorenz Gerbeth,
  • Juliette Roels,
  • Frederik Heinrich,
  • Nils Müller,
  • Pawel Durek,
  • Nikolaus Deigendesch,
  • James Ziai,
  • Jeffrey Hung,
  • Thomas Conrad,
  • Imke Atreya,
  • Raja Atreya,
  • Petra Bacher,
  • Christoph Becker,
  • Christian Bojarski,
  • Nathalie Britzen-Laurent,
  • Caroline Bosch-Voskens,
  • Hyun-Dong Chang,
  • Andreas Diefenbach,
  • Claudia Günther,
  • Ahmed N. Hegazy,
  • Kai Hildner,
  • Christoph S. N. Klose,
  • Kristina Koop,
  • Susanne Krug,
  • Moritz Leppkes,
  • Rocío López-Posadas,
  • Leif S.-H. Ludwig,
  • Clemens Neufert,
  • Markus Neurath,
  • Jay Patankar,
  • Magdalena Prüß,
  • Andreas Radbruch,
  • Francesca Ronchi,
  • Ashley Sanders,
  • Alexander Scheffold,
  • Jörg-Dieter Schulzke,
  • Sebastian Schürmann,
  • Michael Stürzl,
  • Zlatko Trajanoski,
  • Antigoni Triantafyllopoulou,
  • Maximilian Waldner,
  • Carl Weidinger,
  • Sebastian Zundler,
  • Anja A. Kühl,
  • Stefan Wirtz,
  • Max Löhning,
  • Mary Keir,
  • Andreas Diefenbach,
  • Mir-Farzin Mashreghi,
  • Britta Siegmund,
  • Michael Schumann,
  • Chiara Romagnani,
  • Nathaniel R. West,
  • Ahmed N. Hegazy

摘要

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.