Hirotoshi Kataoka

Migration of CD4 T Cells and Dendritic Cells toward Sphingosine 1-Phosphate (S1P) Is Mediated by Different Receptor Subtypes: S1P Regulates the Functions of Murine Mature Dendritic Cells via S1P Receptor Type 3

Dendritic cells (DCs) and lymphocytes are known to show a migratory response to the phospholipid mediator, sphingosine 1-phosphate (S1P). However, it is unclear whether the same S1P receptor subtype mediates the migration of lymphocytes and DCs toward S1P. In this study, we investigated the involvement of S1P receptor subtypes in S1P-induced migration of CD4 T cells and bone marrow-derived DCs in mice. A potent S1P receptor agonist, the (S)-enantiomer of FTY720-phosphate [(S)-FTY720-P], at 0.1 nM or higher and a selective S1P receptor type 1 (S1P1) agonist, SEW2871, at 0.1 μM or higher induced a dose-dependent down-regulation of S1P1. The pretreatment with these compounds resulted in a significant inhibition of mouse CD4 T cell migration toward S1P. Thus, it is revealed that CD4 T cell migration toward S1P is highly dependent on S1P1. Mature DCs, when compared with CD4 T cells or immature DCs, expressed a relatively higher level of S1P3 mRNA. S1P at 10–1000 nM induced a marked migration and significantly enhanced the endocytosis of FITC-dextran in mature but not immature DCs. Pretreatment with (S)-FTY720-P at 0.1 μM or higher resulted in a significant inhibition of S1P-induced migration and endocytosis in mature DCs, whereas SEW2871 up to 100 μM did not show any clear effect. Moreover, we found that S1P-induced migration and endocytosis were at an extremely low level in mature DCs prepared from S1P3-knockout mice. These results indicate that S1P regulates migration and endocytosis of murine mature DCs via S1P3 but not S1P1.

A New Phenylpyrazoleanilide, Y-320, Inhibits Interleukin 17 Production and Ameliorates Collagen-Induced Arthritis in Mice and Cynomolgus Monkeys

Interleukin (IL)-15 and IL-17 are thought to play an important role in the pathogenesis of rheumatoid arthritis (RA) because both pro-inflammatory cytokines are found in synovial fluid of RA patients. In this study, we examined the pharmacological profiles of Y-320, a new phenylpyrazoleanilide immunomodulator. Y-320 inhibited IL-17 production by CD4 T cells stimulated with IL-15 with IC50 values of 20 to 60 nM. Oral administration of Y-320 (0.3 to 3 mg/kg) significantly inhibited the development and progression of arthritis and joint destruction with reduction of IL-17 mRNA expression in arthritic joints of type II collagen-induced arthritis (CIA) in DBA/1J mice. Y-320 in combination with anti-murine tumor necrosis factor-α monoclonal antibody showed a synergistic effect on mouse CIA. Moreover, therapeutic treatment with Y-320 (0.3 and 1 mg/kg orally) ameliorated CIA in cynomolgus monkeys. Our results suggest that Y-320, an orally active inhibitor for IL-17 production, provides a useful therapy for RA.

Therapeutic Effects of the Sphingosine 1-Phosphate Receptor Modulator, Fingolimod (FTY720), on Experimental Autoimmune Encephalomyelitis

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720, fingolimod hydrochloride) is an orally active sphingosine 1-phosphate (S1P) receptor modulator with a structure closely related to sphingosine (Adachi et al., 1995; Chiba et al., 1996, 1997) (Fig. 1). FTY720 sequesters circulating mature lymphocytes into the secondary lymphoid organs (SLO) and thymus by long-term down-regulation of S1P receptor type 1 (S1P1) on lymphocytes, and shows potent immunomodulating effects (Brinkmann et al., 2000, 2002a, 2002b, 2004; Chiba et al., 1998, 1999, Chiba, 2005; Matloubian et al., 2004).