A novel sphingosine 1-phosphate receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), regulates chronic colitis in interleukin-10 gene-deficient mice.
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-gamma, IL-12, and tumor necrosis factor-alpha 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.
Song
Jinghai
J
Department of Complementary and Alternative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Matsuda
Chu
C
Kai
Yasuyuki
Y
Nishida
Toshirou
T
Nakajima
Kiyokazu
K
Mizushima
Tsunekazu
T
Kinoshita
Miki
M
Yasue
Tokutaro
T
Sawa
Yoshiki
Y
Ito
Toshinori
T
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*
D016207:Cytokines; D007166:Immunosuppressive Agents; C501899:KRP-203; D049349:Receptors, Lysosphingolipid; D013438:Sulfhydryl Compounds; D016753:Interleukin-10; D002118:Calcium