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–/–) mouse model. KRP-203 agonistic activity on S1P receptor was assessed in vitro. KRP-203 was administered for 1 or 4 weeks to IL-10–/– mice with clinical signs of colitis. The histological appearance of the colon and the numbers, phenotype, and cytokine production of lymphocytes were compared with a control group. KRP-203 treatment was effective in preventing body weight loss in the IL-10–/– colitis model. One-week administration resulted in the sequestration of circulating lymphocytes within the secondary lymphoid tissues. After 4 weeks of treatment, highly significant reductions were observed in number of CD4+ T cell and B220+ B cell subpopulations in the lamina propria of the colon and peripheral blood. KRP-203 obviously inhibited the production of interferon-γ, IL-12, and tumor necrosis factor-α by the colonic lymphocytes, but had no influence on IL-4 production. KRP-203 significantly inhibits ongoing IL-10–/– colitis in part through decreasing the infiltration of lymphocytes at inflammatory sites and by blocking T-helper 1 cytokine production in the colonic mucosa. Therefore, the possibility arises that KRP-203 plays a potential role in control of chronic colitis.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.119172.
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ABBREVIATIONS: CD, Crohn's disease; IBD, inflammatory bowel disease; IL, interleukin; IL-10–/–, interleukin 10 gene-deficient; LP, lamina propria; TH, T helper; IFN, interferon; FTY720, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride, C19H33NO2; TNF, tumor necrosis factor; S1P, sphingosine 1-phosphate; PP, Payer's patch(es); MLN, mesenteric lymph node; PB, peripheral blood; KRP-203, 2-amino-2-{2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl}-1,3-propanediol hydrochloride, C24H26ClNO3S; CHO, Chinese hamster ovary; -P, phosphorylated; SP, spleen; CLP, colonic lamina propria; mAb, monoclonal antibody; NF-κB, nuclear factor-κB.
- Received December 25, 2006.
- Accepted September 25, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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