Expression of interferon alfa signaling components in human alcoholic liver disease.
Expression of interferon alfa signaling components in human alcoholic liver disease.
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干扰素α信号成分在人类酒精性肝病中的表达。
DOI：
10.1053/jhep.2002.31169
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Gao,Bin
中科院分区：
文献类型：
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作者：
Nguyen,Van-Anh;Gao,Bin
干扰素α（IFN-α）是目前唯一成熟的治疗病毒性肝炎的药物。然而，其有效性在酒精中毒患者中大大降低（< 10%）。这种抵抗的机制尚未完全了解。本研究检测了9例酒精性肝病（ALD）和8例健康对照肝组织中IFN-α信号组分及其抑制因子的表达。与正常对照肝脏相比，ALD肝脏中IFN-β、IFN-α受体1/2、Jak 1和Tyk 2的表达保持不变，而IFN-α、信号转导和转录激活因子1（STAT 1）和p48的表达上调，STAT 2的表达下调。在携带流感病毒抗性等位基因Mx+和2 '-5'寡腺苷酸合成酶（OAS）蛋白的小鼠细胞中，IFN诱导的抗病毒MxA（一种75 kd的嗜核蛋白）的表达不受调节，而在ALD肝脏中，双链RNA激活的蛋白激酶（PKR）的表达降低了55%。在ALD肝脏中检查了JAK-STAT信号通路的三个抑制因子家族。细胞因子信号传导抑制因子（SOCS）家族的成员，包括SOCS 1、2、3和CIS，以及蛋白酪氨酸磷酸酶，包括Shp-1、Shp-2和CD 45，在ALD肝脏中没有上调，而p42/44丝裂原活化蛋白激酶的磷酸化和蛋白水平与正常对照肝相比，ALD肝中p42/44 MAP激酶的表达分别增加约3.9倍和3.2倍。总之，这些结果表明，慢性饮酒下调STAT 2和PKR，但上调p42/44丝裂原活化蛋白激酶（p42/44 MAP激酶），这可能导致ALD患者肝脏中IFN-α信号转导的下调。
Interferon alfa (IFN-α) is currently the only well-established therapy for viral hepatitis. However, its effectiveness is much reduced (< 10%) in alcoholic patients. The mechanism underlying this resistance is not fully understood. In this study, we examined the expression of IFN-α signaling components and its inhibitory factors in 9 alcoholic liver disease (ALD) and 8 healthy control liver tissues. In comparison with normal control livers, expression of IFN-β, IFN-α receptor ½, Jak1, and Tyk2 remained unchanged in ALD livers, whereas expression of IFN-α, signal transducer and activator of transcription factor 1 (STAT1), and p48 were up-regulated and expression of STAT2 was down-regulated. Expression of antiviral MxA a karyophilic 75 kd protein induced by IFN in mouse cells carrying the influenza virus resistance allele Mx+ and 2'-5'oligoadenylate synthetase (OAS) proteins was not regulated, whereas expression of double-stranded RNA-activated protein kinase (PKR) was decreased by 55% in ALD livers. Three families of inhibitory factors for the JAK-STAT signaling pathway were examined in ALD livers. Members of the suppressor of cytokine signaling (SOCS) family, including SOCS 1, 2, 3, and CIS, and the protein tyrosine phosphatases, including Shp-1, Shp-2, and CD45, were not up-regulated in ALD livers, whereas the phosphorylation of and protein levels of p42/44 mitogen-activated protein kinase (p42/44MAP kinase) were increased about 3.9-and 3.2-fold in ALD livers in comparison with normal control livers, respectively. In conclusion, these findings suggest that chronic alcohol consumption down-regulates STAT2 and PKR, but up-regulates p42/44 mitogen-activated protein kinase (p42/44MAP kinase), which may cause down-regulation of IFN-α signaling in the liver of ALD patients.