Postoperative ileus involves interleukin-1 receptor signaling in enteric glia

Gastroenterology. 2014 Jan;146(1):176-87.e1. doi: 10.1053/j.gastro.2013.09.030. Epub 2013 Sep 22.


Background & aims: Postoperative ileus (POI) is a common consequence of abdominal surgery that increases the risk of postoperative complications and morbidity. We investigated the cellular mechanisms and immune responses involved in the pathogenesis of POI.

Methods: We studied a mouse model of POI in which intestinal manipulation leads to inflammation of the muscularis externa and disrupts motility. We used C57BL/6 (control) mice as well as mice deficient in Toll-like receptors (TLRs) and cytokine signaling components (TLR-2(-/-), TLR-4(-/-), TLR-2/4(-/-), MyD88(-/-), MyD88/TLR adaptor molecule 1(-/-), interleukin-1 receptor [IL-1R1](-/-), and interleukin (IL)-18(-/-) mice). Bone marrow transplantation experiments were performed to determine which cytokine receptors and cell types are involved in the pathogenesis of POI.

Results: Development of POI did not require TLRs 2, 4, or 9 or MyD88/TLR adaptor molecule 2 but did require MyD88, indicating a role for IL-1R1. IL-1R1(-/-) mice did not develop POI; however, mice deficient in IL-18, which also signals via MyD88, developed POI. Mice given injections of an IL-1 receptor antagonist (anakinra) or antibodies to deplete IL-1α and IL-1β before intestinal manipulation were protected from POI. Induction of POI activated the inflammasome in muscularis externa tissues of C57BL6 mice, and IL-1α and IL-1β were released in ex vivo organ bath cultures. In bone marrow transplantation experiments, the development of POI required activation of IL-1 receptor in nonhematopoietic cells. IL-1R1 was expressed by enteric glial cells in the myenteric plexus layer, and cultured primary enteric glia cells expressed IL-6 and the chemokine monocyte chemotactic protein 1 in response to IL-1β stimulation. Immunohistochemical analysis of human small bowel tissue samples confirmed expression of IL-1R1 in the ganglia of the myenteric plexus.

Conclusions: IL-1 signaling, via IL-1R1 and MyD88, is required for development of POI after intestinal manipulation in mice. Agents that interfere with the IL-1 signaling pathway are likely to be effective in the treatment of POI.

Keywords: GFAP; GI; Gastrointestinal Dysmotility; IL; IL-1 receptor antagonist; IL-18R; IL-1R; IL-1R1; IL-1ra; IM; Ig; Inflammatory Response; Innate Immunity; MCP-1; ME; MPO; POI; Pathogen Recognition; TLR; Toll-like receptor; WT; gastrointestinal; glial fibrillary acidic protein; immunoglobulin; interleukin; interleukin 1 receptor; interleukin-1 receptor type I; interleukin-18 receptor; intestinal manipulation; mRNA; messenger RNA; monocyte chemotactic protein 1; muscularis externa; myeloperoxidase; postoperative ileus; wild-type.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Disease Models, Animal
  • Gastrointestinal Motility / immunology*
  • Ileus / immunology*
  • Ileus / metabolism
  • Interleukin-1 / immunology*
  • Interleukin-1 / metabolism
  • Interleukin-18 / genetics
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Smooth / immunology*
  • Muscle, Smooth / metabolism
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology*
  • Myeloid Differentiation Factor 88 / metabolism
  • Myenteric Plexus / immunology*
  • Myenteric Plexus / metabolism
  • Neuroglia / immunology*
  • Neuroglia / metabolism
  • Postoperative Complications / immunology*
  • Postoperative Complications / metabolism
  • Receptors, Interleukin-1 Type I / genetics
  • Receptors, Interleukin-1 Type I / immunology*
  • Receptors, Interleukin-1 Type I / metabolism
  • Signal Transduction
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism


  • IL1R1 protein, mouse
  • Interleukin-1
  • Interleukin-18
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin-1 Type I
  • Toll-Like Receptors