Intrahepatic IL-8 producing Foxp3+CD4+ regulatory T cells and fibrogenesis in chronic hepatitis C
Intrahepatic IL-8 producing Foxp3+CD4+ regulatory T cells and fibrogenesis in chronic hepatitis C
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DOI：
10.1016/j.jhep.2013.04.011
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发表时间：
2013-08-01
影响因子：
25.7
通讯作者：
Spengler, Ulrich
中科院分区：
文献类型：
--
作者：
Langhans, Bettina;Kraemer, Benjamin;Spengler, Ulrich
背景和目标：调节性CD 4（+）T细胞（TCRs）被认为影响HCV感染的结果，因为它们在慢性丙型肝炎期间数量增加并且可以抑制T细胞功能。方法：使用微阵列分析，原位免疫荧光，ELISA和流式细胞术，我们描述了慢性丙型肝炎患者适应性TCRs的功能分化和定位。我们发现慢性丙型肝炎患者Foxp 3（+）CD 4（+）T细胞中IL-8显著上调。活化的GARP阳性IL-8（+）T细胞在慢性丙型肝炎患者的肝纤维化区域附近特别富集，其数量与纤维化阶段相关。此外，TGF 3诱导原代人肝星状细胞（HSC）中促纤维化标志物TIMP 1、MMP 2、TGF-β 1、α-SMA、胶原和CCL 2的上调。加入中和IL-8抗体可阻断HSC的激活，但不阻断Treg抑制功能。结论：我们的研究确定Foxp 3（+）CD 4（+）T细胞作为慢性丙型肝炎作用于HSC的IL-8的额外肝内来源。因此，慢性丙型肝炎中的Foxp 3（+）CD 4（+）T细胞除了抑制局部免疫反应外，还作为纤维形成的调节因子获得了分化。(C)2013年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions.Methods: Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C.Results: We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody.Conclusions: Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.