The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes.
The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes.
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DOI：
10.4049/jimmunol.0803206
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Szabo G
中科院分区：
文献类型：
--
作者：
Mandrekar P;Bala S;Catalano D;Kodys K;Szabo G
酒精使用后宿主防御功能受损与细胞因子产生变化有关，然而，急性和慢性酒精对单核/巨噬细胞激活的调节不同。我们推测，在人单核细胞中，急性酒精诱导对内毒素的低反应性，导致肿瘤坏死因子-α降低，而慢性酒精通过对内毒素的增敏而增加肿瘤坏死因子-α。我们发现，急性酒精增加了人单核细胞中IL-1R相关的单核细胞(IRAK-M)，IRAK-M是IRAK-1的负调节因子。这与内毒素刺激后IκBα激酶活性、核因子κBDNA结合和核因子κB驱动的报告活性降低有关。相反，慢性酒精降低了IRAK-M的表达，但增加了IRAK-1和IKK激酶的活性、核因子κBDNA结合和核因子κB报告活性。用小干扰核糖核酸抑制急性酒精暴露单核细胞的IRAK-M可恢复内毒素诱导的肿瘤坏死因子-α的产生，而慢性酒精巨噬细胞的IRAK-M过表达则阻止肿瘤坏死因子-α的增加。在慢性酒精暴露中，添加酒精代谢抑制剂不会改变脂多糖信号和肿瘤坏死因子-α的产生。IRAK-1激活可诱导MAPK，在肿瘤坏死因子-α的诱导过程中起重要作用。急性酒精可降低单核细胞内ERK的活性，而慢性酒精可增加单核细胞内ERK的活性，而ERK抑制剂PD98059可阻止慢性酒精引起的肿瘤坏死因子-α的升高。综上所述，急性酒精抑制脂多糖诱导的NFERK B和κ活化导致单核细胞对脂多糖的低反应性，这是由于IRAK-M增加所致。相反，慢性酒精通过减少IRAK-M的表达和激活NFERK B和κ激酶而使单核细胞对内毒素敏感。我们的数据表明，IRAK-M通过单核细胞中不同长度的酒精暴露，在对内毒素信号的相反调节中起着核心作用。
Impaired host defense after alcohol use is linked to altered cytokine production, however, acute and chronic alcohol differently modulate monocyte/macrophage activation. We hypothesized that in human monocytes, acute alcohol induces hyporesponsiveness to LPS, resulting in decreased TNF-α, whereas chronic alcohol increases TNF-α by sensitization to LPS. We found that acute alcohol increased IL-1R-associated kinase-monocyte (IRAK-M), a negative regulator of IRAK-1, in human monocytes. This was associated with decreased IκBα kinase activity, NFκB DNA binding, and NFκB-driven reporter activity after LPS stimulation. In contrast, chronic alcohol decreased IRAK-M expression but increased IRAK-1 and IKK kinase activities, NFκB DNA binding, and NFκB-reporter activity. Inhibition of IRAK-M in acute alcohol-exposed monocytes using small interfering RNA restored the LPS-induced TNF-α production whereas over-expression of IRAK-M in chronic alcohol macrophages prevented the increase in TNF-α production. Addition of inhibitors of alcohol metabolism did not alter LPS signaling and TNF-α production during chronic alcohol exposure. IRAK-1 activation induces MAPKs that play an important role in TNF-α induction. We determined that acute alcohol decreased but chronic alcohol increased activation of ERK in monocytes and ERK inhibitor, PD98059, prevented the chronic alcohol-induced increase in TNF-α. In summary, inhibition of LPS-induced NFκB and ERK activation by acute alcohol leads to hyporesponsiveness of monocytes to LPS due to increased IRAK-M. In contrast, chronic alcohol sensitizes monocytes to LPS through decreased IRAK-M expression and activation of NFκB and ERK kinases. Our data indicate that IRAK-M is a central player in the opposite regulation of LPS signaling by different lengths of alcohol exposure in monocytes.
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DOI：
10.1111/j.1530-0277.2008.00726.x
发表时间：
2008-09
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Norkina O;Dolganiuc A;Catalano D;Kodys K;Mandrekar P;Syed A;Efros M;Szabo G
通讯作者：
Szabo G
DOI：
10.1097/00005373-200011000-00003
发表时间：
2000-11-01
影响因子：
--
作者：
Heagy, W;Hansen, C;West, MA
通讯作者：
West, MA
影响因子：
2.3
作者：
Karavitis, John;Murdoch, Eva L.;Kovacs, Elizabeth J.
通讯作者：
Kovacs, Elizabeth J.
影响因子：
4.4
作者：
Mandrekar, Pranoti;Jeliazkova, Valentina;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi
影响因子：
8.8
作者：
Cuschieri, J;Maier, RV
通讯作者：
Maier, RV