Abstract |
Loss of intestinal epithelial barrier function including typical tight junction changes and epithelial cell apoptosis plays an important role in Crohn's disease. SEW2871, a selective sphingosine-1-phosphate type-1 receptor agonist, has been proven to be efficient in protecting against colitis in IL-10(-/-) mice in our previous study. Here we performed additional studies to investigate whether treatment with SEW2871 was associated with an improved epithelial barrier function in IL-10(-/-) mice. SEW2871 was administered by gavage at a dose of 20 mg/kg/day for 2 weeks to IL-10(-/-) mice. Severity of colitis, CD4+ T cells in colon lamina propria and proinflammatory cytokine productions were evaluated. Furthermore, intestinal permeability, tight junction ( occludin and ZO-1) expressions and distributions, as well as epithelial cell apoptosis, were also assessed. SEW2871 treatment attenuated established colitis associated with decreased CD4+ T cells in colon lamina propria and reduced TNF-α and IFN-γ levels. Moreover, enhanced barrier function, which resulted from ameliorated tight junction ( occludin and ZO-1) expressions and suppressed epithelial cell apoptosis, was found to contribute to the therapeutic effects. SEW2871 treatment protects from colitis in IL-10(-/-) mice through reduced epithelial cell apoptosis and improved barrier function. Thus, targeting sphingosine-1-phosphate may represent a new therapeutic approach in Crohn's disease.
|
Authors | Jianning Dong, Honggang Wang, Jie Zhao, Jing Sun, Tenghui Zhang, Lugen Zuo, Weiming Zhu, Jianfeng Gong, Yi Li, Lili Gu, Jieshou Li |
Journal | Immunologic research
(Immunol Res)
Vol. 61
Issue 3
Pg. 303-11
(Mar 2015)
ISSN: 1559-0755 [Electronic] United States |
PMID | 25588868
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Cytokines
- Immunosuppressive Agents
- Oxadiazoles
- Receptors, Lysosphingolipid
- S1pr1 protein, mouse
- SEW2871
- Sphingosine-1-Phosphate Receptors
- Thiophenes
- Interleukin-10
|
Topics |
- Animals
- Apoptosis
(drug effects, genetics)
- CD4-Positive T-Lymphocytes
(drug effects, immunology)
- Colitis
(drug therapy)
- Colon
(drug effects, physiology)
- Crohn Disease
(drug therapy)
- Cytokines
(metabolism)
- Epithelial Cells
(drug effects, pathology)
- Humans
- Immunosuppressive Agents
(administration & dosage)
- Interleukin-10
(genetics)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Animal
- Oxadiazoles
(administration & dosage, pharmacology)
- Receptors, Lysosphingolipid
(agonists)
- Sphingosine-1-Phosphate Receptors
- Thiophenes
(administration & dosage, pharmacology)
- Tight Junctions
(drug effects, genetics)
|