Toll-like receptor 3 and suppressor of cytokine signaling proteins regulate CXCR4 and CXCR7 expression in bone marrow-derived human multipotent stromal cells.
Toll-like receptor 3 and suppressor of cytokine signaling proteins regulate CXCR4 and CXCR7 expression in bone marrow-derived human multipotent stromal cells.
复制标题
DOI：
10.1371/journal.pone.0039592
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Betancourt AM
中科院分区：
文献类型：
--
作者：
Tomchuck SL;Henkle SL;Coffelt SB;Betancourt AM
近年来，骨髓来源的人多能基质细胞（hMSC）在基于细胞的治疗中的使用急剧增加，因为研究人员已经利用这些细胞迁移到组织损伤，炎症和肿瘤部位的能力。我们的研究小组确定，hMSC通过激活Toll样受体（TLR）对“危险”信号（受损，感染或发炎组织的副产品）做出反应。然而，关于hMSC中TLR介导的下游信号传导知之甚少。我们证明TLR 3刺激激活Janus激酶（JAK）2/信号转导和转录激活因子（STAT）1通路，并增加hMSC中细胞因子信号转导抑制因子（SOCS）1和SOCS 3的表达。我们的研究表明，这些SOCS中的每一个都在负调控TLR 3和JAK/STAT信号传导中发挥着独特的作用。TLR 3介导的干扰素调节因子1（IRF 1）的表达受到SOCS 3过表达的抑制，而SOCS 1过表达减少STAT 1的激活。此外，我们的研究首次证明，当TLR 3在hMSC中被激活时，CXCR 4和CXCR 7的表达下调。SOCS 3过表达抑制TLR 3刺激后CXCR 4和CXCR 7的内化。相反，SOCS 1过表达仅抑制CXCR 7内化。这些结果表明，SOCS 1和SOCS 3在调节hMSC中的TLR 3、JAK/STAT和CXCR 4/CXCR 7信号传导中各自发挥功能上不同的作用，并进一步阐明了hMSC对危险信号的反应方式。
The use of bone marrow-derived human multipotent stromal cells (hMSC) in cell-based therapies has dramatically increased in recent years, as researchers have exploited the ability of these cells to migrate to sites of tissue injury, inflammation, and tumors. Our group established that hMSC respond to “danger” signals – by-products of damaged, infected or inflamed tissues – via activation of Toll-like receptors (TLRs). However, little is known regarding downstream signaling mediated by TLRs in hMSC. We demonstrate that TLR3 stimulation activates a Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 1 pathway, and increases expression of suppressor of cytokine signaling (SOCS) 1 and SOCS3 in hMSC. Our studies suggest that each of these SOCS plays a distinct role in negatively regulating TLR3 and JAK/STAT signaling. TLR3-mediated interferon regulatory factor 1 (IRF1) expression was inhibited by SOCS3 overexpression in hMSC while SOCS1 overexpression reduced STAT1 activation. Furthermore, our study is the first to demonstrate that when TLR3 is activated in hMSC, expression of CXCR4 and CXCR7 is downregulated. SOCS3 overexpression inhibited internalization of both CXCR4 and CXCR7 following TLR3 stimulation. In contrast, SOCS1 overexpression only inhibited CXCR7 internalization. These results demonstrate that SOCS1 and SOCS3 each play a functionally distinct role in modulating TLR3, JAK/STAT, and CXCR4/CXCR7 signaling in hMSC and shed further light on the way hMSC respond to danger signals.
登录
查看更多内容
影响因子：
6.5
作者：
Dai, Xiuju;Sayama, Koji;Hashimoto, Koji
通讯作者：
Hashimoto, Koji
DOI：
10.2217/17584272.4.1.57
发表时间：
2009-02-01
期刊：
International journal of clinical rheumatology
影响因子：
--
作者：
Niyibizi C;Li F
通讯作者：
Li F
DOI：
10.1073/pnas.0900244106
发表时间：
2009-03-10
影响因子：
11.1
作者：
Coffelt, Seth B.;Marini, Frank C.;Scandurro, Aline B.
通讯作者：
Scandurro, Aline B.
影响因子：
32.4
作者：
Nakagawa, R;Naka, T;Kishimoto, T
通讯作者：
Kishimoto, T
影响因子：
168.9
作者：
Askari, AT;Unzek, S;Penn, MS
通讯作者：
Penn, MS