Therapeutic Effects Of SEW2871,a Sphingosine-1-phosphate Type 1 Receptor Agonist,on Experimental Colitis In Interleukin-10 Gene Deficient Mice

Background:Crohn's disease(CD),one of the major forms of inflammatory bowel disease,is generally considered as a chronic inflammatory disorder associated with a dysregulated mucosal immune response.Although tremendous progress has been made in our understanding of the pathogenesis of CD,its precise etiology still remains unclear.Despite of this,increasing evidence suggests that an imbalanced mucosal T cell response may play an important role in the pathogenesis of CD.IL-10 gene deficient(IL-10-/-)mice spontaneously develop Crohn's-like chronic colitis when bred and maintained under specific-pathogen-free(SPF)conditions,with massive infiltration of activated lymphocytes and macrophages in the lamina propria(LP)of the colon,accompanied by a CD4+Thl and Th17 response with secreting tumor necrosis factor(TNF)-?,IL-1?,IL-12,interferon(IFN)-?,and IL-17A.High levels of p-STAT3 and adhesion moleculer ICAM-1 and MAdCAM-1 in colon tissues of IL-1 0-/-mice were also observed.Moreover,previous studies have shown that IL-10-/-mice exhibited a dysregulated barrier function with elevations in colonic permeability and increased epithelial apoptosis when compared with wild type controls.Sphingosine-1-phosphate(SIP),primarily regarded as an intermediate of sphingolipid metabolism,is now recognized as a powerful mediator of many vital cellular processes.S1P is recognized by cells expressing S1P receptors.Of the five types of S1P receptor,type 1 S1P receptors(S1P1)are preferentially expressed by lymphocytes,and they determine lymphocyte emigration from and retention in the lymphoid tissues.Accumulating evidence has revealed the pivotal role of S1P in the development of inflammatory diseases such as autoimmune type 1 diabetes,rheumatoid arthritis,and multiple sclerosis.SEW2871,a selective S1P1 agonist,was found to induce lymphopenia in mice via a S1P 1-dependent mechanism.SEW2871 has already been proven to be efficient in protecting kidneys against ischemia-reperfusion injury and preserving renal function by reducing CD4+T cell infiltration in mice.However,the effects of SEW2871 on colitis remain unclear.Aims:The aim of this study was to investigate the effects of SEW2871 on established colitis in interleukin-10 gene deficient(IL-10-/-)mice,a murine model of Crohn's disease(CD).Methods:SEW2871 was administered by gavage at a dose of 20 mg/kg/d for 2 weeks to IL-10-/-mice.After mice were sacrificed,severity of colitis,serum amyloid A,tissue myeloperoxidase(MPO),T cells in blood and colon lamina propria(LP),proinflammatory cytokine productions were evaluated.Furthermore,the phospho-STAT3(p-STAT3)expression,adhension molecules ICAM-1 and MAdCAM-1 mRNA expressions,tight junction(occludin and ZO-1)expressions and distributions,as well as epithelial cell apoptosis were also assessed.Results:The 2-week administration of SEW2871 ameliorated established colitis in IL-10-1-mice,associated with a reduction of serum amyloid A concentration,a decreased colon MPO concentration,a depletion of the peripheral CD4+CD45+T cells and a reduction of the homing of T cells into colon LP.Typical cytokines of Thl and Th17 cells,p-STAT3 expression and ICAM-1,MAdCAM-1 expressions were also suppressed by SEW2871 treatment.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.Conclusions:SEW2871 treatment ameliorates established experimental colitis in IL-10-/-mice,which may provide a new therapeutic approach for human CD therapy.