A novel sphingosine-1-phosphate receptor agonist KRP-203 attenuates rat autoimmune myocarditis

Sphingosine-1-phosphate (S1P) is an active sphingolipid metabolite that exerts important biological effects. Recently, we demonstrated that KRP-203 is a novel S1P receptor agonist that can alter lymphocyte homing and act as an immunomodulating agent. We investigated the efficacy of KRP-203 in the tr...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2007-09, Vol.361 (3), p.621-628
Main Authors: Ogawa, Ryo, Takahashi, Masafumi, Hirose, Sho-ichi, Morimoto, Hajime, Ise, Hirohiko, Murakami, Takashi, Yasue, Tokutaro, Kuriyama, Kazuhiko, Hongo, Minoru, Kobayashi, Eiji, Ikeda, Uichi
Format: Article
Language:English
Subjects:
Animals
Autoimmune Diseases - drug therapy
Autoimmune Diseases - metabolism
Body Weight
Cardiomyocyte
CD4-Positive T-Lymphocytes - metabolism
Cytokine
Cytokines - metabolism
Disease Models, Animal
Echocardiography
Flow Cytometry
Immunohistochemistry
Inflammation
Inflammation - metabolism
Leukocytes - metabolism
Lymphocyte
Male
Myocarditis - drug therapy
Myocarditis - immunology
Myocarditis - metabolism
Rats
Rats, Inbred Lew
Receptors, Lysosphingolipid - agonists
Receptors, Lysosphingolipid - metabolism
Sulfhydryl Compounds - therapeutic use
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Summary:Sphingosine-1-phosphate (S1P) is an active sphingolipid metabolite that exerts important biological effects. Recently, we demonstrated that KRP-203 is a novel S1P receptor agonist that can alter lymphocyte homing and act as an immunomodulating agent. We investigated the efficacy of KRP-203 in the treatment of rat experimental autoimmune myocarditis. KRP-203 significantly attenuated the inflammation area, heart weight/body weight ratio, and left ventricular function. Immunohistochemical analysis and RT-PCR revealed that KRP-203 significantly decreased the infiltration of macrophages and CD4 T cells in the myocardium and the expression of inflammatory cytokines. Flow cytometric analysis revealed that treatment with KRP-203 effectively reduced the number of peripheral CD4 and CD8 T cells but not that of B cells and granulocytes. Further, late KRP-203 treatment was effective even against established EAM. These results demonstrate the therapeutic potential of KRP-203 for the treatment of human myocarditis and provide new insights into the pathogenesis of this disease.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2007.07.061