An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4.
An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4.
复制标题
DOI：
10.1084/jem.20021897
复制
发表时间：
2003-06-02
期刊：
影响因子：
--
通讯作者：
Romagnani P
中科院分区：
文献类型：
--
作者：
Lasagni L;Francalanci M;Annunziato F;Lazzeri E;Giannini S;Cosmi L;Sagrinati C;Mazzinghi B;Orlando C;Maggi E;Marra F;Romagnani S;Serio M;Romagnani P
趋化因子CXCL9/Mig、CXCL10/IP-10和CXCL11/i-TAC调节淋巴细胞的趋化作用，介导血管周细胞的增殖，作为血管抑制剂，从而抑制肿瘤的生长。这些多重活动显然是由一种独特的G蛋白偶联受体CXCR3介导的。趋化因子CXCL4/PF4与CXCL9、CXCL10和CXCL11具有共同的活性，包括强大的血管抑制作用，但其特异性受体尚不清楚。在这里，我们描述了一个独特的，以前未被识别的受体CXCR3-B，它来自CXCR3基因的另一种剪接，它介导CXCR3配体的血管抑制活性，也是CXCL4的功能性受体。将已知的CXCR3(更名为CXCR3-A)或CXCR3-B导入人微血管内皮细胞系-1(HMEC-1)，结合CXCL9、CXCL10和CXCL11，而CXCL4仅与CXCR3-B具有高亲和力。CXCR3-A的过表达导致细胞存活率增加，而CXCR3-B的过表达通过激活不同的信号转导通路显著减少DNA合成和上调HMEC-1的凋亡。值得注意的是，被CXCL9、CXCL10、CXCL11和CXCL4抑制生长的人微血管内皮细胞原代培养表达CXCR3-B，但不表达CXCR3-A。最后，为选择性识别CXCR3-B而产生的单抗与肿瘤组织中的内皮细胞反应，提供了CXCR3-B在体内表达的证据，并可能解释了CXC趋化因子的血管抑制作用。
The chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC regulate lymphocyte chemotaxis, mediate vascular pericyte proliferation, and act as angiostatic agents, thus inhibiting tumor growth. These multiple activities are apparently mediated by a unique G protein–coupled receptor, termed CXCR3. The chemokine CXCL4/PF4 shares several activities with CXCL9, CXCL10, and CXCL11, including a powerful angiostatic effect, but its specific receptor is still unknown. Here, we describe a distinct, previously unrecognized receptor named CXCR3-B, derived from an alternative splicing of the CXCR3 gene that mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4. Human microvascular endothelial cell line-1 (HMEC-1), transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B. Overexpression of CXCR3-A induced an increase of survival, whereas overexpression of CXCR3-B dramatically reduced DNA synthesis and up-regulated apoptotic HMEC-1 death through activation of distinct signal transduction pathways. Remarkably, primary cultures of human microvascular endothelial cells, whose growth is inhibited by CXCL9, CXCL10, CXCL11, and CXCL4, expressed CXCR3-B, but not CXCR3-A. Finally, monoclonal antibodies raised to selectively recognize CXCR3-B reacted with endothelial cells from neoplastic tissues, providing evidence that CXCR3-B is also expressed in vivo and may account for the angiostatic effects of CXC chemokines.
登录
查看更多内容
DOI：
10.1084/jem.184.3.963
发表时间：
1996-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Loetscher M;Gerber B;Loetscher P;Jones SA;Piali L;Clark-Lewis I;Baggiolini M;Moser B
通讯作者：
Moser B
影响因子：
4.8
作者：
ARONICA, SM;MANTEL, C;BROXMEYER, HE
通讯作者：
BROXMEYER, HE
影响因子：
13.6
作者：
Gröne, HJ;Cohen, CD;Nelson, PJ
通讯作者：
Nelson, PJ
影响因子：
4.8
作者：
Maghazachi, AA;Skalhegg, BS;AlAoukaty, A
通讯作者：
AlAoukaty, A
DOI：
10.1084/jem.182.1.219
发表时间：
1995-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Luster AD;Greenberg SM;Leder P
通讯作者：
Leder P