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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Epimorphin(-/-) mice are protected, in part, from acute colitis via decreased interleukin 6 signaling
Anisa Shaker1, Matthew Gargus1, Julie Fink2
1Divisions of Gastroenterology and Hepatology, Keck School of Medicine of USC, Los Angeles, CA.
Abstract:
Epimorphin (Epim), a member of the syntaxin family of membrane-bound, intracellular vesicle-docking proteins, is expressed in intestinal myofibroblasts and macrophages. We demonstrated previously that Epimorphin(-/-)(Epim(-/-)) mice are protected, in part, from dextran sodium sulfate (DSS)-induced colitis. Although interleukin (IL)-6/p-Stat3 signaling has been implicated in the pathogenesis of colitis, the myofibroblast contribution to IL-6 signaling in colitis remains unexplored. Our aim was to investigate the IL-6 pathway in Epim(-/-) mice in the DSS colitis model. Whole colonic tissue, epithelium, and stroma of WT and congenic Epim(-/-) mice treated with 5% DSS for 7 days were analyzed for IL-6 and a downstream effector, p-Stat3, by immunostaining and immunoblot. Colonic myofibroblast and peritoneal macrophage IL-6 secretion were evaluated by enzyme-linked immunosorbent assay. IL-6 and p-Stat3 expression were decreased in Epim(-/-) vs WT colon. A relative increase in stromal vs epithelial p-Stat3 expression was observed in WT mice but not in Epim(-/-) mice. Epim deletion abrogates IL-6 secretion from colonic myofibroblasts treated with IL-1β and decreases IL-6 secretion from peritoneal macrophages in a subset of DSS-treated mice. Epim deletion inhibits IL-6 secretion most profoundly from colonic myofibroblasts. Distribution of Stat3 activation is altered in DSS-treated Epim(-/-) mice. Our findings support the notion that myofibroblasts modulate IL-6/p-Stat3 signaling in DSS-treated Epim(-/-) mice.
Insights
Epimorphin deletion in mice reduces IL-6/p-Stat3 signaling in the colon, particularly from myofibroblasts, offering protection against dextran sodium sulfate-induced colitis.
Area of Science:
- Gastroenterology
- Immunology
- Cell Biology
Background:
- Epimorphin (Epim) is a syntaxin family protein found in intestinal myofibroblasts and macrophages.
- Epim(-/-) mice show partial protection against dextran sodium sulfate (DSS)-induced colitis.
- The role of myofibroblasts in IL-6/p-Stat3 signaling during colitis is not well understood.
Purpose of the Study:
- To investigate the impact of Epim deletion on the IL-6/p-Stat3 pathway in DSS-induced colitis.
- To determine the contribution of colonic myofibroblasts to IL-6 signaling in this model.
Main Methods:
- Analysis of IL-6 and p-Stat3 expression in colonic tissues (whole, epithelial, stromal) from WT and Epim(-/-) mice treated with DSS.
- Immunostaining and immunoblotting techniques were employed.
- Measurement of IL-6 secretion from isolated colonic myofibroblasts and peritoneal macrophages using ELISA.
Main Results:
- IL-6 and p-Stat3 expression were significantly decreased in the colons of Epim(-/-) mice compared to WT mice.
- Epim deletion abrogated IL-6 secretion from IL-1β-stimulated colonic myofibroblasts and reduced it in peritoneal macrophages from a subset of DSS-treated mice.
- A shift in the distribution of Stat3 activation was observed in DSS-treated Epim(-/-) mice.
Conclusions:
- Myofibroblasts play a crucial role in modulating IL-6/p-Stat3 signaling in the context of DSS-induced colitis.
- Epim deletion profoundly inhibits IL-6 secretion from colonic myofibroblasts, impacting Stat3 activation.
- These findings highlight Epimorphin as a potential therapeutic target in inflammatory bowel diseases.
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