Acute alcohol exposure exerts anti-inflammatory effects by inhibiting IκB kinase activity and p65 phosphorylation in human monocytes
Acute alcohol exposure exerts anti-inflammatory effects by inhibiting IκB kinase activity and p65 phosphorylation in human monocytes
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DOI：
10.4049/jimmunol.178.12.7686
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
--
作者：
Mandrekar, Pranoti;Jeliazkova, Valentina;Szabo, Gyongyi
急性饮酒与免疫反应受损和促炎细胞因子产生减少有关。我们早期的研究表明，急性酒精摄入以一种不依赖于I kappa BA的方式抑制NF-kappa B DNA结合。我们利用人外周血单核细胞和转导CD14细胞的中国仓鼠卵巢细胞，报道了体外急性酒精处理通过破坏p65的磷酸化而抑制了核因子-kappaB的表达。P65和I kappaB免疫沉淀结果显示，急性酒精暴露1h后，胞浆内的NF-kappa B-I kappa Bα复合体减少。P65在Ser516上的磷酸化是由I kappa B激酶(IKK)β介导的，并且是依赖于NF-kappa B的细胞反应所必需的。我们发现，急性酒精处理降低了脂多糖诱导的IKKα和IKKβ的活性，导致p65在Ser(536)处的磷酸化减少。此外，酒精处理后Ikka的核表达增加，这可能有助于抑制核转录因子-kB的表达。Ser 276处核p65的磷酸化降低可能不是由于酒精诱导的蛋白激酶A和丝裂原和应激激活的蛋白激酶-1活性的抑制。虽然急性酒精处理后I kappa Bα磷酸化降低是由于IKK)3活性降低，但酒精暴露期间I kappa Bα的降解不依赖于ikkβ。在26S蛋白酶体抑制剂存在的情况下，酒精诱导的I kappa B的降解提示蛋白酶体非依赖性的I kappa Bα的降解。总而言之，我们的研究表明，急性酒精暴露主要通过影响p65的磷酸化来调节I kappa Bα非依赖性的NF-kappa B活性。这些发现进一步暗示了ikk beta在酒精对免疫细胞的急性影响中扮演的重要角色。
Acute alcohol use is associated with impaired immune responses and decreased proinflammatory cytokine production. Our earlier studies have shown that acute alcohol intake inhibits NF-kappa B DNA binding in an I kappa Ba-independent manner. We report using human peripheral blood monocytes and Chinese hamster ovary cells transfected with CD14 cells that acute alcohol treatment in vitro exerts NF-kappa B inhibition by disrupting phosphorylation of p65. Immunoprecipitation of p65 and I kappa Ba revealed that acute alcohol exposure for 1 h decreased NF-kappa B-I kappa B alpha complexes in the cytoplasm. Phosphorylation of p65 at Ser 516 is mediated by I kappa B kinase (IKK)beta and is required for NF-kappa B-dependent cellular responses. We show that acute alcohol treatment decreased LPS-induced IKK alpha and IKK beta activity resulting in decreased phosphorylation of p65 at Ser(536). Furthermore, nuclear expression of IKKa increased after alcohol treatment, which may contribute to inhibition of NF-KB.. Decreased phosphorylation of nuclear p65 at Ser 276 was likely not due to alcohol-induced inhibition of protein kinase A and mitogen- and stress-activated protein kinase-1 activity. Although decreased I kappa B alpha phosphorylation after acute alcohol treatment was attributable to reduced IKK)3 activity, degradation of I kappa B alpha during alcohol exposure was IKK beta-independent. Alcohol-induced degradation of I kappa Ba in the presence of a 26S proteasome inhibitor suggested proteasome-independent I kappa B alpha degradation. Collectively, our studies suggest that acute alcohol exposure modulates I kappa B alpha-independent NF-kappa B activity primarily by affecting phosphorylation of p65. These findings further implicate an important role for IKK beta in the acute effects of alcohol in immune cells.