Acute alcohol intake induces SOCS1 and SOCS3 and inhibits cytokine-induced STAT1 and STAT3 signaling in human monocytes.
Acute alcohol intake induces SOCS1 and SOCS3 and inhibits cytokine-induced STAT1 and STAT3 signaling in human monocytes.
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DOI：
10.1111/j.1530-0277.2008.00726.x
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发表时间：
2008-09
期刊：
影响因子：
--
通讯作者：
Szabo G
中科院分区：
文献类型：
--
作者：
Norkina O;Dolganiuc A;Catalano D;Kodys K;Mandrekar P;Syed A;Efros M;Szabo G
急性饮酒与免疫抑制细胞因子的诱导和对各种病原体的促炎反应的下调有关。我们之前报道过酒精激活janus激酶/信号转换器和转录激活因子（JAK/STAT）信号导致IL-10诱导。JAK-STAT通路也激活其自身的负调节因子，细胞因子信号（SOCS） 1和SOCS3的抑制因子。SOCS蛋白是诱导抑制剂，负调控细胞因子、IL-6或ifn诱导的STAT3/STAT1信号通路。本研究旨在探讨急性酒精对人单核细胞中IL-6或IFNs诱导的SOCS1/SOCS3和STAT3/STAT1通路调控的影响。在正常志愿者每千克体重饮用2毫升伏特加酒前和24小时后采集血样。体外实验用乙醇预处理人单核细胞，然后用细胞因子刺激；Western blot检测蛋白，EMSA检测核蛋白与DNA结合，real - time PCR检测RNA。结果：急性体内或体外酒精处理均增加单核细胞中SOCS1和SOCS3 RNA的表达。酒精处理导致STAT3和STAT1 DNA结合能力增加。STAT1和STAT3的激活均可诱导SOCS1/3。我们假设酒精诱导SOCS蛋白反过来可能通过STAT1和STAT3调节细胞因子信号传导。事实上，我们观察到IL-6、IFNα和ifn γ诱导的STAT1 DNA结合的显著下调，以及IL-6和ifn γ诱导的STAT3的抑制，当酒精在细胞因子刺激前3小时加入单核细胞。在酒精预处理的细胞中，IL-6诱导的STAT3 DNA结合受到抑制，IL-6刺激后，IL-6依赖性基因MCP-1和ICAM-1的水平降低。与单独EtOH类似，EtOH+IL-6联合模拟导致SOCS3和SOCS1基因的表达增加。虽然急性酒精治疗单独激活STAT1/3信号通路并诱导单核细胞中SOCS3和SOCS1水平，但酒精也会通过STAT1/STAT3通路下调IL-6， IFNα-和ifn γ-诱导的信号通路，可能是通过过度激活SOCS。
Acute alcohol consumption is associated with induction of immuno-inhibitory cytokines and down-regulation of pro-inflammatory responses to various pathogens. We previously reported that alcohol activates janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling leading to IL-10 induction. The JAK-STAT pathway also activates its own negative regulators, suppressors of cytokine signaling (SOCS) 1 and SOCS3. SOCS proteins are inducible inhibitors that negatively regulate STAT3/STAT1 signaling pathways induced by cytokines, IL-6 or IFNs. Here we aimed to explore the effect of acute alcohol on induction of SOCS1/SOCS3 and regulation of STAT3/STAT1 pathways induced by IL-6 or IFNs in human monocytes. Blood samples from normal volunteers were collected before and 24 hours after consumption of 2 ml vodka/kg body weight. For in vitro experiments human monocytes were pretreated with ethanol (EtOH) followed by stimulation with cytokines; proteins were analyzed by Western blot, nuclear protein binding to DNA by EMSA, and RNA by real time PCR. Results: Acute in vivo or in vitro alcohol treatment increased both SOCS1 and SOCS3 RNA expression in monocytes. Alcohol treatment resulted in increased STAT3 and STAT1 DNA binding capacity. Activation of both STAT1 and STAT3 has been shown to induce SOCS1/3. We hypothesized that induction of SOCS proteins by alcohol in turn may lead to modulation of cytokine signaling through STAT1 and STAT3. Indeed, we observed significant down-regulation of IL-6-, IFNα- and IFNγ-induced STAT1 DNA binding as well as inhibition of IL-6- and IFNγ-induced STAT3 when alcohol was added to monocytes 3 hours prior to the cytokine stimulation. Consistent with inhibition of IL-6-induced STAT3 DNA binding in alcohol-pretreated cells, the levels of IL-6-dependent genes, MCP-1 and ICAM-1, was reduced after IL-6 stimulation. Similar to EtOH alone, combined EtOH+IL-6 simulation resulted in increased expression of both SOCS3 and SOCS1 genes. While acute alcohol treatment alone activates STAT1/3 signaling pathways and induces SOCS3 and SOCS1 levels in monocytes, alcohol also leads to down-regulation of IL-6-, IFNα-, and IFNγ-induced signaling via STAT1/STAT3 pathways, likely through excessive SOCS activation.
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影响因子：
4.8
作者：
Gatto, L;Berlato, C;Bazzoni, F
通讯作者：
Bazzoni, F
影响因子：
2.3
作者：
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作者：
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影响因子：
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作者：
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通讯作者：
Szabo, Gyongyi
影响因子：
4.4
作者：
Federici, M;Giustizieri, ML;Albanesi, C
通讯作者：
Albanesi, C