Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice.
Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice.
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DOI：
10.1002/hep.24190
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发表时间：
2011-04
期刊：
影响因子：
13.5
通讯作者：
Gao, Bin
中科院分区：
文献类型：
--
作者：
Jeong, Won-Il;Park, Ogyi;Suh, Yang-Gun;Byun, Jin-Seok;Park, So-Young;Choi, Earl;Kim, Ja-Kyung;Ko, Hyojin;Wang, Hua;Miller, Andrew M.;Gao, Bin
天然免疫的激活(自然杀伤细胞/干扰素-γ：NK细胞/干扰素-γ)已被证明在抗病毒、抗肿瘤防御以及抗纤维化中发挥着重要作用。然而，对于先天性免疫在慢性肝损伤中的调节作用，人们知之甚少。在这里，我们比较了NK细胞在四氯化碳(CCl4)攻击2周和10周诱导的早期和晚期肝纤维化中的功能。注射聚I：C或干扰素-γ诱导2周CCl_4模型小鼠肝星状细胞(HSC)的NK细胞活化和NK细胞杀伤。这种激活在10周的CCl4模型中减弱。与这些发现一致的是，在10周的模型中，聚I：C和干扰素-γ对肝纤维化的抑制作用明显低于2周的CCL4模型。体外共培养实验表明，培养4天(早期激活)的HSC通过NKG2D-维甲酸诱导的早期基因1(RAe1)依赖机制诱导NK细胞活化。当HSC与培养8天(中等激活)的HSC共同培养时，由于HSC产生转化生长因子-β(转化生长因子-β)，这种激活被降低。此外，早期激活的HSC是敏感的，而中等激活的HSC对干扰素-γ介导的细胞增殖抑制具有抵抗力，这可能是由于细胞因子信号转导抑制因子1(SOCS1)的表达增加所致。SOCS1基因的破坏恢复了干扰素-γ对中等激活的HSCs细胞增殖的抑制作用。HSCs产生视黄醇代谢产物参与SOCS1的诱导，继而抑制干扰素-γ信号和功能，而HSCs产生转化生长因子-β抑制NK细胞功能和对HSCs的细胞毒作用。在晚期肝损伤中，NK细胞/干扰素-γ的抗纤维化作用受到抑制，这可能是由于中等激活的HSC中转化生长因子-β的产生和SOCS1的表达增加所致。
Activation of innate immunity (natural killer cell/interferon-γ: NK cell/IFN-γ) has been shown to play an important role in anti-viral and anti-tumor defenses as well as anti-fibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10 week-carbon tetrachloride (CCl4) challenge, respectively. Injection of poly I:C or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl4 model. Such activation was diminished in the 10-week CCl4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week vs. the 2-week CCl4 model. In vitro co-culture experiments demonstrated that 4-day cultured (early-activated) HSCs induce NK cell activation via an NKG2D-retinoic acid-induced early gene 1 (RAE1)-dependent mechanism. Such activation was reduced when co-cultured with 8-day cultured (intermediately-activated) HSCs due to the production of transforming growth factor-β (TGF-β) by HSCs. Moreover, early-activated HSCs were sensitive, while intermediately-activated HSCs were resistant to IFN-γ mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately-activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, while production of TGF-β by HSCs inhibited NK cell function and cytotoxicity against HSCs. The anti-fibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to the increased production of TGF-β and expression of SOCS1 in intermediately-activated HSCs.
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影响因子：
3.9
作者：
Natarajan, SK;Thomas, S;Balasubramanian, KA
通讯作者：
Balasubramanian, KA
影响因子：
13.5
作者：
Hellemams, K;Verbuyst, P;Geerts, A
通讯作者：
Geerts, A
影响因子：
2.5
作者：
Muir, AJ;Sylvestre, PB;Rockey, DC
通讯作者：
Rockey, DC
DOI：
10.1016/j.bbrc.2005.01.110
发表时间：
2005-04-01
影响因子：
3.1
作者：
Choi, WH;Ji, KA;Joe, EH
通讯作者：
Joe, EH
影响因子：
5.1
作者：
Duester, G;Mic, FA;Molotkov, A
通讯作者：
Molotkov, A