Postoperative ileus involves interleukin-1 receptor signaling in enteric glia.
Gastroenterology
; 146(1): 176-87.e1, 2014 Jan.
Article
in En
| MEDLINE
| ID: mdl-24067878
ABSTRACT
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-1ß 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-1ß 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-1ß 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.Key words
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
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Postoperative Complications
/
Neuroglia
/
Interleukin-1
/
Ileus
/
Myeloid Differentiation Factor 88
/
Receptors, Interleukin-1 Type I
/
Gastrointestinal Motility
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Muscle, Smooth
/
Myenteric Plexus
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Gastroenterology
Year:
2014
Document type:
Article
Affiliation country:
Germany