Department of Liver Transplantation, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Int Immunopharmacol. 2012 Jan;12(1):189-96. doi: 10.1016/j.intimp.2011.11.010. Epub 2011 Dec 7.
In the presence of TGF-β, 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-1β) and tumor necrosis factor alpha (TNF-α). Ex vivo study indicated that iTregs suppressed IL-1β and TNF-α expression, promoted transcription of interleukin-10 (IL-10), and elevated phosphorylation of SMAD3 in Kupffer cells (KCs). Furthermore, inhibition of TGF-β signaling by anti-TGF-β abolished the effects on KCs. Treatment with TGF-β 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-β.
在 TGF-β 的存在下，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，我们已经表明，iTregs 的过继转移促进了缺血再灌注损伤（IRI）后的肝脏恢复。在这项研究中，我们在小鼠部分肝IRI 模型中检查了 iTregs 减轻肝IRI 的分子机制。我们发现，再灌注后 24 小时，肝 Tregs 群体显著减少。IRI 前过继转移 iTregs 可显著增加肝 Tregs 的数量，并减轻肝IRI，表现为血清转氨酶和促炎细胞因子（如白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α））减少。体外研究表明，iTregs 抑制 IL-1β和 TNF-α的表达，促进白细胞介素-10（IL-10）的转录，并增加库普弗细胞（KCs）中 SMAD3 的磷酸化。此外，抗 TGF-β 信号转导抑制 TGF-β 可消除对 KCs 的影响。TGF-β 处理可抑制 KCs 中基质金属蛋白酶（MMP9）的产生并保护肝脏免受 IRI。总之，我们的结果表明，iTregs 通过调节 TGF-β 来调节 KCs 的促炎和抗炎功能，在肝 IRI 中发挥关键作用。
