Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal Inflammation

Gastroenterology. 2019 Mar;156(4):1082-1097.e11. doi: 10.1053/j.gastro.2018.11.029. Epub 2018 Nov 16.


Background & aims: Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) that frequently results in functional damage, bowel obstruction, and surgery. Interleukin (IL) 36 is a group of cytokines in the IL1 family with inflammatory effects. We studied the expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in the development of intestinal fibrosis in human tissues and mice.

Methods: We obtained intestinal tissues from 92 patients with Crohn's disease (CD), 48 patients with ulcerative colitis, and 26 patients without inflammatory bowel diseases (control individuals). Tissues were analyzed by histology to detect fibrosis and by immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R, and we studied intestinal tissues from Il1rl2-/- mice; colitis and fibrosis were induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2-/- to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied.

Results: Mucosal and submucosal tissue from patients with CD or ulcerative colitis had higher levels of collagens, including type VI collagen, compared with tissue from control individuals. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed α-smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2-/- mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis after administration of DSS or TNBS, but bone marrow cells from Il1rl2-/- mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation.

Conclusion: We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD compared with control individuals. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R gene in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD.

Keywords: Cytokine Signaling; Disease Progression; IBD; IL-36; IL36; α-SMA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Case-Control Studies
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / pathology
  • Colitis, Ulcerative / metabolism*
  • Colitis, Ulcerative / pathology
  • Collagen Type VI / metabolism*
  • Colon / pathology*
  • Crohn Disease / metabolism*
  • Crohn Disease / pathology
  • Dextran Sulfate
  • Fibroblasts / drug effects
  • Fibrosis
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Humans
  • Interleukin-1 / metabolism*
  • Interleukin-1 / pharmacology
  • Intestinal Mucosa / pathology*
  • Intestine, Small / pathology*
  • Ligands
  • Mice
  • Mice, Knockout
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism*
  • Signal Transduction
  • Transcriptome
  • Trinitrobenzenesulfonic Acid


  • ACTA2 protein, human
  • Actins
  • Antibodies, Neutralizing
  • Collagen Type VI
  • IL1RL2 protein, human
  • IL36A protein, human
  • Interleukin-1
  • Ligands
  • Receptors, Interleukin-1
  • alpha-smooth muscle actin, mouse
  • interleukin 36, human
  • interleukin-36 receptor, mouse
  • interleukin-36, mouse
  • Trinitrobenzenesulfonic Acid
  • Dextran Sulfate