Sphingosine-1-phosphate receptor agonists suppress concanavalin A-induced hepatic injury in mice
Sphingosine-1-phosphate receptor agonists suppress concanavalin A-induced hepatic injury in mice
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DOI：
10.1016/j.bbrc.2006.04.067
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发表时间：
2006-06-23
影响因子：
3.1
通讯作者：
Kobayashi, Eiji
中科院分区：
文献类型：
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作者：
Kaneko, Takashi;Murakami, Takashi;Kobayashi, Eiji
T细胞介导的免疫应答在包括自身免疫性肝炎在内的各种肝损伤中起关键作用。将刀豆球蛋白A（Con A）注射到小鼠体内模拟T细胞介导的肝炎的组织学和病理表型。在器官移植的宿主免疫控制方面的最新进展包括鞘氨醇-1-磷酸（SIP）受体激动剂如FTY 720的开发，其改变淋巴细胞归巢但不抑制宿主全身免疫。在此，我们检查了新的SIP受体激动剂KRP-203对Con A诱导的肝损伤模型的作用。FTY 720和KRP 203均能促进正常BALB/c小鼠肝淋巴细胞向次级淋巴结的转移，并显著降低肝淋巴细胞数（p < 0.05）。基于这一观察结果，在Con A诱导的肝炎模型中使用KRP 203。KRP 203显著减少了渗入Con A处理的肝脏的CD 4（+）淋巴细胞的数量（p < 0.05），并成功地降低了血清转氨酶升高（p = 0.017），因此保护了小鼠免受Con A诱导的肝损伤。有趣的是，这种归巢调节较少发生在通过趋化因子受体CXCR 4的天然肝T细胞归巢中。因此，S1 P受体激动剂优先靶向CXCR 4（+）CD 4（+）外周血T淋巴细胞，并抑制Con A诱导的肝炎的发生，表明它们对T细胞介导的肝损伤的治疗有效性。(c)2006年爱思唯尔公司All rights reserved.
T cell-mediated immune responses play a critical role in a variety of liver injuries including autoimmune hepatitis. Injection of concanavalin A (Con A) into mice mimics the histological and pathological phenotype of T cell-mediated hepatitis. Recent advances in host immune control of organ transplantation include the development of sphingosine-1-phosphate (SIP) receptor agonists such as FTY720, which alter lymphocyte homing but do not suppress host general immunity. Herein we examined the effect of the new SIP receptor agonist KRP-203 on the Con A-induced liver damage model. In normal liver lymphocytes of BALB/c mice, both FTY720 and KRP203 promoted lymphocyte sequestering from the liver to secondary lymph nodes and significantly reduced the number of liver lymphocytes (p < 0.05). Based on this observation, KRP203 was employed in the Con A-induced hepatitis model. KRP203 markedly reduced the number of CD4(+) lymphocytes that infiltrate Con A-treated liver (p < 0.05) and successfully reduced serum transaminase elevation (p = 0.017), therefore protecting mice from Con A-induced liver injury. Interestingly this homing modulation less occurs in natural hepatic T cell homing through the chemokine receptor, CXCR4. Therefore, S1P receptor agonists preferentially target CXCR4(+)CD4(+) peripheral blood T lymphocytes and suppress the occurrence of Con A-induced hepatitis, suggesting their therapeutic usefulness against T cell-mediated hepatic injury. (c) 2006 Elsevier Inc. All rights reserved.