Ex vivo induced regulatory T cells regulate inflammatory response of Kupffer cells by TGF-beta and attenuate liver ischemia reperfusion injury
Ex vivo induced regulatory T cells regulate inflammatory response of Kupffer cells by TGF-beta and attenuate liver ischemia reperfusion injury
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DOI：
10.1016/j.intimp.2011.11.010
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发表时间：
2012-01-01
影响因子：
5.6
通讯作者：
Lu, Ling
中科院分区：
文献类型：
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作者：
Feng, Min;Wang, Quanrongzi;Lu, Ling
在tgf - β存在下，CD4+CD62L+T细胞可被诱导为CD4+CD25+FoxP3 +调节性T细胞（iTregs）。在我们之前的工作中，我们已经证明iTregs过继性转移促进肝脏从缺血再灌注损伤（IRI）中恢复。在这项研究中，我们在小鼠部分肝脏IRI模型中研究了iTregs抑制肝脏IRI的分子机制。我们发现，在再灌注后24小时，肝脏Tregs的数量明显减少。通过降低血清转氨酶和促炎细胞因子，如白细胞介素-1 β (IL-1 β)和肿瘤坏死因子α (tnf - α)， IRI前过继移植iTregs可显著增加肝脏treg的数量，减轻肝脏IRI。体外研究表明，iTregs抑制IL-1 β和tnf - α的表达，促进白细胞介素-10 （IL-10）的转录，并升高KCs中SMAD3的磷酸化。此外，抗tgf - β对tgf - β信号的抑制消除了对KCs的影响。tgf - β治疗可抑制KCs中基质金属蛋白酶（MMP9）的产生，并保护肝脏免受IRI。总之，我们的研究结果表明，iTregs通过tgf - β调节KCs的促炎和抗炎功能，在肝脏IRI中发挥关键作用。爱思唯尔B.V.版权所有
In the presence of TGF-beta, CD4+CD62L+T cells can be induced to CD4+CD25+FoxP3 + regulatory T cells (iTregs). In our previous work, we have shown that adoptive transfer of iTregs promoted liver recovery from ischemia reperfusion injury (IRI). In this study, we examined the molecular mechanism underlying the liver IRI attenuation by iTregs in a mouse partial hepatic IRI model. We found that the population of hepatic Tregs decreased significantly at 24 h after reperfusion. Adoptive transfer of iTregs before IRI markedly increased the numbers of hepatic Tregs and attenuated liver IRI as indicated by reduced serum aminotransferases and proinflammatory cytokines, such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha). Ex vivo study indicated that iTregs suppressed IL-1 beta and TNF-alpha expression, promoted transcription of interleukin-10 (IL-10), and elevated phosphorylation of SMAD3 in Kupffer cells (KCs). Furthermore, inhibition of TGF-beta signaling by anti-TGF-beta abolished the effects on KCs. Treatment with TGF-beta, suppressed matrix metalloprotease (MMP9) production in KCs and protected liver from IRI. In conclusion, our results suggest that iTregs play a critical role in hepatic IRI by regulating pro-inflammatory and anti-inflammatory function of KCs through TGF-beta. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.