SEW2871 protects from experimental colitis through reduced epithelial cell apoptosis and improved barrier function in interleukin-10 gene-deficient mice

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.

GPR120, a potential therapeutic target for experimental colitis in IL-10 deficient mice

“…Western blotting of protein expressions was performed in details as described previously [34, 35]. The primary antibodies against TAK1, IKK-α, IkB-α and p65 were all purchased from Abcam.…”

Inflammatory Conditions Disrupt Constitutive Endothelial Cell Barrier Stabilization by Alleviating Autonomous Secretion of Sphingosine 1-Phosphate

“…Previous studies investigated the influence of S1PR1 agonists on EC barrier protection in various different disease models with mixed results. While some studies showed beneficial effects [7,25], others reported they were ineffective [26]. Thus far, even successful approaches with S1PR1 agonists were not very effective.…”

Transcriptional modulation of SLC26A3 (DRA) by sphingosine-1-phosphate

“…This barrier-protective effect of S1P was attributed to an increase in level and distribution of E-cadherin (18). Recent studies showed that oral treatment of S1P agonist protected experimental colitis by improving tight junction-dependent barrier function (11). However, there are no studies pertaining to its effects on intestinal epithelial absorptive processes, which are fundamental to diarrhea associated with IBD (33).…”

“…S1P is known to regulate the gut immune system in both health and disease states (22) and has been reported to inhibit gastrointestinal injury in response to radiation or chemically induced colitis (4). This protection was conferred via sphingosine-1-phosphate receptor (S1PR) signaling at least in colitis (11). But mechanistic details of the underlying processes are not well understood.…”