TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability

Mucosal Immunol. 2022 Apr;15(4):698-716. doi: 10.1038/s41385-022-00506-x. Epub 2022 Apr 5.


Successful treatment of chronic inflammatory diseases integrates both the cessation of inflammation and the induction of adequate tissue repair processes. Strikingly, targeting a single proinflammatory cytokine, tumor necrosis factor (TNF), induces both processes in a relevant cohort of inflammatory bowel disease (IBD) patients. However, the molecular mechanisms underlying intestinal repair following TNF blockade during IBD remain elusive. Using a novel humanized model of experimental colitis, we demonstrate that TNF interfered with the tissue repair program via induction of a soluble natural antagonist of IL-22 (IL-22Ra2; IL-22BP) in the colon and abrogated IL-22/STAT3-mediated mucosal repair during colitis. Furthermore, membrane-bound TNF expressed by T cells perpetuated colonic inflammation, while soluble TNF produced by epithelial cells (IECs) induced IL-22BP expression in colonic dendritic cells (DCs) and dampened IL-22-driven restitution of colonic epithelial functions. Finally, TNF induced IL-22BP expression in human monocyte-derived DCs and levels of IL22-BP correlated with TNF in sera of IBD patients. Thus, our data can explain how anti-TNF therapy induces mucosal healing by increasing IL-22 availability and implicates new therapeutic opportunities for IBD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Availability
  • Colitis* / metabolism
  • Colon / pathology
  • Humans
  • Inflammation / metabolism
  • Inflammatory Bowel Diseases* / metabolism
  • Interleukin-22
  • Interleukins
  • Intestinal Mucosa / metabolism
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha / metabolism


  • Interleukins
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha