TITLE:
Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —II
AUTHORS:
Noriyasu Seki, Hirotoshi Kataoka, Kunio Sugahara, Atsushi Fukunari, Kenji Chiba
KEYWORDS:
Sphingosine 1-Phosphosphate Receptor 1; Fingolimod Hydrochloride (FTY720); Experimental Autoimmune Encephalomyelitis; Astrocytes; Pro-Inflammatory Cytokines
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.4 No.8,
November
26,
2013
ABSTRACT:
Therapeutic administration of
fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine
1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on
experimental autoimmune encephalomyelitis (EAE) induced by myelin
oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed
an only partial inhibition
of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting
that down-regulation of lymphocytic S1P1 is insufficient to explain the
therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic
administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial
fibrillary acidic protein, an activation marker of astrocytes, in the CNS of
EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was
higher as compared with those of the other S1P receptor subtypes and
phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an
S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of
S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes.
S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly
and treatment with FTY720-P or SEW2871 inhibited production of these
pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results
suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by
astrocytes. Consequently, it is highly probable that the therapeutic effects of
FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th
cells from the draining lymph nodes but also activation of astrocytes in the
CNS.