Silencing S1P1 receptors regulates collagen-V reactive lymphocyte-mediated immunobiology in the transplanted lung
Silencing S1P1 receptors regulates collagen-V reactive lymphocyte-mediated immunobiology in the transplanted lung
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DOI：
10.1111/j.1600-6143.2007.02116.x
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发表时间：
2008-03-01
影响因子：
8.8
通讯作者：
Wilkes, D. S.
中科院分区：
文献类型：
--
作者：
Chiyo, M.;Iwata, T.;Wilkes, D. S.
V型胶原（col[V]）反应性淋巴细胞有助于肺移植排斥反应，但迁移到移植物中的机制尚不清楚。鞘氨醇-1-磷酸-1受体（S1 P（1 R））在其他研究中被认为是淋巴细胞迁移所必需的，但它们在col（V）反应性淋巴细胞排斥反应中的作用尚不清楚。利用小干扰RNA（siRNA）降低col（V）反应性淋巴细胞上S1 P（1 R）的表达，我们研究了S1 P（1 R）在排斥反应中的作用。定量聚合酶链反应（PCR）显示免疫大鼠分离的col（V）反应性淋巴细胞上S1 P（1 R）信使RNA（mRNA）的强表达。S1 P（1 R）特异性siRNA（S1 P（1 R）siRNA）可降低S1 P（1 R）mRNA和蛋白的表达，而scramble siRNA（SC siRNA）则无此作用。与暴露于SC siRNA的细胞相比，用S1 P（1 R）siRNA处理的淋巴细胞连续转移至大鼠Wistar京都（WKY）肺同种移植受体导致细胞保留在肝脏内，纵隔淋巴结中的细胞较少。S1 P（1 R）缺陷细胞对同种异体抗原有应答而增殖，但对col（V）无应答，并且与对照相比，对col（V）有应答而产生较少的干扰素（IFN）-γ。下调S1 P（1 R）并不影响白细胞介素（IL）-10和肿瘤坏死因子（TNF）-α的产生，也不影响对迁移至关重要的粘附分子的表达，但可预防排斥病理学，并降低过继转移后IFN-γ的局部水平。这些数据证明了S1 P（1 R）的新作用，包括调节迁移和调节淋巴细胞活化。
Type V collagen (col[V])-reactive lymphocytes contribute to lung transplant rejection, but the mechanisms for emigration into the graft are unknown. Sphingosine-1-phosphate-1 receptors (S1P(1R)) are believed to be required for lymphocyte emigration in other studies, but their role in col(V)-reactive lymphocyte rejection responses is not known. Utilizing small interfering RNA (siRNA) to reduce S1P(1R) expression on col(V)-reactive lymphocytes, we examined the role of S1P(1R) in the rejection response. Quantitative polymerase chain reaction (PCR) revealed strong expression of S1P(1R) messenger RNA (mRNA) on col(V)-reactive lymphocytes isolated from immunized rats. S1P(1R)-specific siRNA (S1P(1R) siRNA) reduced expression of S1P(1R) mRNA and protein, whereas scramble siRNA (SC siRNA) had no effect. Adoptive transfer of lymphocytes treated with S1P(1R) siRNA to rat Wistar Kyoto (WKY) lung isograft recipients resulted in retention of cells within the liver with fewer cells in mediastinal lymph nodes when compared to cells exposed to SC siRNA. S1P(1R)-deficient cells proliferated in response to alloantigens, but not in response to col(V), and produced less interferon (IFN)-gamma in response to col(V) compared to controls. Downregulating S1P(1R) did not affect production of interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha, or expression of adhesion molecules critical for migration, but prevented rejection pathology and lowered local levels of IFN-gamma post adoptive transfer. These data demonstrate novel roles of S1P(1R,) which include regulating emigration and modulating lymphocyte activation.