Therapeutic Effects of Novel Sphingosine-1-Phosphate Receptor Agonist W-061 in Murine DSS Colitis

Abstract

Although IL-17 is a pro-inflammatory cytokine reportedly involved in various autoimmune inflammatory disorders, its role remains unclear in murine models of colitis. Acute colitis was induced by 2.5% dextran sodium sulfate (DSS) treatment for 5 days. A novel sphingosine-1-phosphate receptor agonist W-061, a prototype of ONO-4641, was orally administered daily, and histopathological analysis was performed on the colon. The number of lymphocytes and their cytokine production were also evaluated in spleen, mesenteric lymph node, Peyer's patch and lamina propria of the colon. Daily administration of W-061 resulted in improvement of DSS-induced colitis, and significantly reduced the number of CD4+ T cells in the colonic lamina propria. Numbers of both Th17 and Th1 cells were reduced by W-061 treatment. W-061, however, had no influence on the number of Treg cells in lamina propria. Thus, Th17 and Th1 cells in lamina propria were thought to be the key subsets in the pathogenesis of DSS-induced colitis. In conclusion, W-061 may be a novel therapeutic strategy to ameliorate acute aggravation of inflammatory bowel diseases.

Perilla frutescens extract ameliorates DSS-induced colitis by suppressing proinflammatory cytokines and inducing anti-inflammatory cytokines

“…In addition, we previously reported in the treatment of DSS for 5 days that Th17 cells significantly increased as early as on day 6 and then decreased on day 10, whereas Th1 cells significantly increased on day 10 with a delay in lamina propria (41). Therefore, we examined the influence of each ingredient on cytokine secretion of splenic mononuclear cells, which consist of macrophages, dendritic cells, and lymphocytes.…”

“…In terms of the immunological aspects in IBD pathogenesis, we have recently shown that a new sphingosine 1-phosphate receptor agonist, W-061, ameliorated colitis induced by suppression of homing of T helper 17 (Th17) into lamina propria with dextran sulfate sodium (DSS) in wild-type mice, which are immunologically competent (41). In this experiment, we confirmed that Th17 and regulatory T cells (Tregs) in lamina propria had some important roles for the pathogenesis of colitis.…”

Sphingolipid metabolites in inflammatory disease

“…In agreement, S1P is elevated during colitis and SphK1 expression is increased in patients with ulcerative colitis 26 . Several studies have also shown that FTY720 and other pharmacological agents that target S1PR1 are very effective in rodent models of colitis 78,110,111 , and several second-generation S1PR1 modulators are currently in clinical trials for patients with ulcerative colitis.…”

Oral treatment with SEW2871, a sphingosine-1-phosphate type 1 receptor agonist, ameliorates experimental colitis in interleukin-10 gene deficient mice

“…Moreover, both KRP-203 and W-061 (another two S1P receptor agonists) were significantly effective in the treatment of chronic ongoing colitis in IL-10 -/-mice and DSS-induced acute colitis, respectively [22,23]. Compared with non-selective S1P receptor agonists, selective S1P1 agonists had the advantage of not inducing bradycardia, as type 3 S1P receptor (S1P3) was implicated directly in this complication [24].…”