Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis.

Abstract

Tumor progression locus-2 (Tpl2) kinase is a major inflammatory mediator in immune cell types recently found to be genetically associated with inflammatory bowel diseases (IBDs). Here we show that Tpl2 may exert a dominant homeostatic rather than inflammatory function in the intestine mediated specifically by subepithelial intestinal myofibroblasts (IMFs). Mice with complete or IMF-specific Tpl2 ablation are highly susceptible to epithelial injury-induced colitis showing impaired compensatory proliferation in crypts and extensive ulcerations without significant changes in inflammatory responses. Following epithelial injury, IMFs sense innate or inflammatory signals and activate, via Tpl2, the cyclooxygenase-2 (Cox-2)-prostaglandin E2 (PGE2) pathway, which we show here to be essential for the epithelial homeostatic response. Exogenous PGE2 administration rescues mice with complete or IMF-specific Tpl2 ablation from defects in crypt function and susceptibility to colitis. We also show that Tpl2 expression is decreased in IMFs isolated from the inflamed ileum of IBD patients indicating that Tpl2 function in IMFs may be highly relevant to human disease. The IMF-mediated mechanism we propose also involves the IBD-associated genes IL1R1, MAPK1, and the PGE2 receptor-encoding PTGER4. Our results establish a previously unidentified myofibroblast-specific innate pathway that regulates intestinal homeostasis and may underlie IBD susceptibility in humans.

• Authors: Manolis Roulis, Christoforos Nikolaou, Elena Kotsaki, Eleanna Kaffe, Niki Karagianni, Vasiliki Koliaraki, Klelia Salpea, Jiannis Ragoussis, Vassilis Aidinis, Eva Martini, Christoph Becker, Harvey R Herschman, Stefania Vetrano, Silvio Danese, George Kollias
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 43 Pg. E4658-67 (Oct 28 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25316791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins
• Dextran Sulfate
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• MAP Kinase Kinase Kinases
• MAP3K8 protein, human
• Map3k8 protein, mouse
• Dinoprostone

Topics

• Animals
• Cell Lineage
• Cell Proliferation (drug effects)
• Colitis (enzymology, immunology, pathology)
• Cyclooxygenase 2 (metabolism)
• Dextran Sulfate
• Dinoprostone (administration & dosage, metabolism, pharmacology)
• Disease Susceptibility
• Enzyme Activation (drug effects)
• Epithelial Cells (drug effects, metabolism, pathology)
• Epithelium (metabolism, pathology)
• Homeostasis (drug effects)
• Humans
• Immunity, Innate (drug effects)
• Inflammation (pathology)
• Inflammatory Bowel Diseases (enzymology, pathology)
• Intestines (pathology)
• MAP Kinase Kinase Kinases (deficiency, metabolism)
• Mice, Inbred C57BL
• Models, Biological
• Myofibroblasts (drug effects, enzymology, metabolism, pathology)
• Phenotype
• Proto-Oncogene Proteins (deficiency, metabolism)
• Signal Transduction (drug effects)