A Novel Sphingosine 1-Phosphate Receptor Agonist, 2-Amino-2-propanediol Hydrochloride (KRP-203), Regulates Chronic Colitis in Interleukin-10 Gene-Deficient Mice

Abstract

Current treatments for patients with Crohn's disease (CD) are based on recent advances in elucidating the pathophysiology of the disease. A satisfactory therapeutic strategy has not been well established. A new sphingosine 1-phosphate (S1P) receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), has been developed for immunomodulation in autoimmune diseases and organ transplantation. We aimed to evaluate the efficacy and potency of KRP-203 on the treatment of chronic colitis in an interleukin (IL)-10 gene-deficient (IL-10

“Inside-Out” Signaling of Sphingosine-1-Phosphate: Therapeutic Targets

“…Furthermore, KRP-203 was highly effective in the treatment of lymphocyte-mediated hepatic injury in mice (Kaneko et al, 2006) and in experimental autoimmune myocarditis (Ogawa et al, 2007). KRP-203 was also found to significantly inhibit ongoing Crohn'slike enterocolitis in an interleukin-10-deficient mouse model (Song et al, 2008). As a selective S1P 1 receptor agonist on lymphocytes, KRP-203 accelerated sequestration of circulating lymphocytes into Peyer's patches and mesenteric lymph nodes, resulting in a reduction of CD4 ϩ T cells at the inflammatory site.…”

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

“…Tregs secrete anti-inflammatory cytokines, such as IL-10 and TGF-␤. IL-10-deficient mice spontaneously develop IBD-like colitis (31,44). In addition, the use of anti-TGF-␤ or anti-IL-10 antibodies exacerbated colitis (2,38,39).…”

KRP-203, Sphingosine 1-Phosphate Receptor Type 1 Agonist, Ameliorates Atherosclerosis in LDL-R −/− Mice

“…Therefore, to narrow down the identity of S1P receptor specifically mediating atheroprotective effects in mice, we used KRP-203-a synthetic compound that shares some structural characteristics with FTY720, but binds with high affinity only to S1PR1. [26][27][28] In rodents, KRP-203 has been effective in preventing transplant rejection. 29 In addition, it ameliorated autoimmune myocarditis in rats, as well as inflammatory liver disease and colitis in mice.…”

“…22,23 However, FTY720, a synthetic S1P analogue and a high-affinity agonist for S1PR1, 3, 4, and 5, was demonstrated to retard atherosclerosis development in both low-density lipoprotein (LDL) receptordeficient (LDL-R −/− ) and apolipoprotein E-deficient mice fed cholesterol-rich Western diet, suggesting that signaling via ≥1 S1P receptors exerts atheroprotective effects in vivo. 24,25 To address the identity of S1P receptor with antiatherogenic activity, we here examined the effect of KRP-203, a synthetic and potent S1PR1 agonist, [26][27][28] on the development of atherosclerosis in LDL-R −/− mice. Our results confirm that activation of S1P signaling pathways inhibits atherosclerosis chiefly by modulating lymphocyte and macrophage function and suggest that S1PR1 at least partly mediates antiatherogenic effects of S1P.…”