Lymphopenia induced by a novel selective S1P₁ antagonist structurally unrelated to S1P

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• 作者：Yasuyuki Fujii^a ; ^{y.fujii@po.rd.taisho.co.jp} ; Hidenori Ohtake^a ; Naoya Ono^a ; Toshifumi Hara^a ; Takanobu Sakurai^a ; Syuya Takahashi^a ; Tetsuo Takayama^a ; Yoshiki Fukasawa^a ; Fumiyasu Shiozawa^a ; Narutoshi Tsukahara^c ; Takehiro Hirayama^c ; Yasuyuki Igarashi^b ; Ryo Goitsuka^c
• 关键词：S1P ; sphingosine 1-phosphate ; S1P1 ; type 1 sphingosine 1-phosphate receptor ; CHS ; contact hypersensitivity response ; HEK293 ; human embryonic kidney cell line ; CHO-K1 ; Chinese hamster ovary cell line ; HTS ; high-throughput screening ; GTP ; guanosine-5&prime
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2012
• 期刊代码：18_13881981
• 类别：bio
• 出版时间：April, 2012
• 卷：1821
• 期：4
• 页码：600-606
• 文件大小：733 K

摘要

Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking via type-1 S1P receptor (S1P₁) and participates in many pathological conditions. We developed a novel type S1P₁-selective antagonist, TASP0251078, which is structurally unrelated to S1P. This competitive antagonist inhibited binding of S1P to S1P₁ resulting in reduced signaling downstream of S1P₁, including GTP纬S-binding and cAMP formation. TASP0251078 also inhibited S1P-induced cellular responses such as chemotaxis and receptor-internalization. Furthermore, when administered in vivo, TASP0251078 induced lymphopenia in blood, which is different from previously reported effects of other S1P₁-antagonists. In a mouse contact hypersensitivity model, TASP0251078 effectively suppressed ear swelling, leukocyte infiltration, and hyperplasia. These findings provide the chemical evidence that S1P₁ antagonism is responsible for lymphocyte sequestration from the blood, and suggest that the effect of S1P₁ agonists on lymphocyte sequestration results from their functional antagonism.