TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes
TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes
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DOI：
10.4049/jimmunol.176.12.7628
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发表时间：
2006-06-15
影响因子：
4.4
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
--
作者：
Oak, Shilpa;Mandrekar, Pranoti;Szabo, Gyongyi
大多数病原体表达共享共同下游信号传导的多种TLR的配体。在这项研究中，我们研究了急性酒精对TLR 2或TLR 4配体及其组合诱导的炎症通路的影响。在人单核细胞中，酒精减弱了TLR 4诱导的TNF-α蛋白和mRNA水平以及NF-κ B活化，但不减弱TLR 2诱导的TNF-α蛋白和mRNA水平以及NF-κ B活化。相反，急性酒精增加TNF-α的生产时，TLR 2和TLR 4配体都存在。IL-1 R相关激酶（IRAK）-1活性降低酒精在TLR 4，但它增加了TLR 2加TLR 4刺激的细胞。IRAK-1的抑制剂IRAK-单核细胞在TLR 4中被诱导，但在TLR 2 + TLR 4刺激的单核细胞中被酒精减少。这得到了TLR 4诱导的IRAK-1：TRAF 6结合减少的支持，但在酒精处理后TLR 2 + TLR 4刺激的单核细胞中IRAK-1：TRAF 6复合物的持续存在。在TLR 4刺激的细胞中，急性酒精选择性抑制MAPK如ERK 1/2的磷酸化。与此相反，JNK磷酸化以及AP-1核结合增强急性酒精在TLR 4和TLR 2联合刺激的存在下。与该结果一致，JNK抑制剂阻止了酒精诱导的TNF-α产生的增加。这些结果表明，急性酒精通过抑制IRAK-1和ERK 1/2激酶以及增加单核细胞中IRAK-单核细胞水平来减弱TLR 4诱导的炎症。相反，在TLR 2和TLR 4配体的存在下，急性酒精通过IRAK-1活化和JNK磷酸化增强炎症反应。因此，TLR介导的信号的复杂性可能决定急性酒精引起的炎症反应的减弱或增强。
Most pathogens express ligands for multiple TLRs that share common downstream signaling. In this study, we investigated the effects of acute alcohol on inflammatory pathways induced by TLR2 or TLR4 ligands and their combination. In human monocytes, alcohol attenuated TLR4- but not TLR2-induced TNF-alpha protein and mRNA levels and NF-kappa B activation. In contrast, acute alcohol augmented TNF-a production when both TLR2 and TLR4 ligands were present. IL-1R-associated kinase (IRAK)-1 activity was reduced by alcohol in TLR4, but it was augmented in TLR2- plus TLR4-stimulated cells. IRAK-monocyte, an inhibitor of IRAK-1, was induced in TLR4, but it was reduced in TLR2- plus TLR4-stimulated monocytes by alcohol. This was supported by decreased IRAK-1:TRAF6 association in TLR4 induced but sustained presence of IRAK-1:TRAF6 complexes in TLR2- plus TLR4-stimulated monocytes after alcohol treatment. Phosphorylation of MAPKs such as ERK1/2 was selectively inhibited by acute alcohol in TLR4-stimulated cells. In contrast, JNK phosphorylation as well as AP-1 nuclear binding were augmented by acute alcohol in the presence of combined TLR4 and TLR2 stimulation. Consistent with this result, the JNK inhibitor prevented alcohol-induced augmentation of TNF-a production. These results suggest that acute alcohol attenuates TLR4-induced inflammation via inhibition of IRAK-1 and ERK1/2 kinases and increases in IRAK-monocyte levels in monocytes. Conversely, in the presence of TLR2 and TLR4 ligands, acute alcohol augments inflammatory responses via IRAK-1 activation and JNK phosphorylation. Thus, the complexity of TLR-mediated signals may determine attenuation or augmentation of inflammatory responses by acute alcohol.