Laval University Cancer Research Center, Quebec City, Quebec G1R 2J6, Canada.
J Biol Chem. 2013 Aug 23;288(34):24948-55. doi: 10.1074/jbc.M113.466334. Epub 2013 Jul 9.
Aliphatic n-alkanols are a family of ubiquitous substances that display general anesthetic properties in accordance to their degree of hydrophobicity. In addition, the immunomodulatory activity of one of its members, ethanol, has long been recognized. We reasoned that because unbranched aliphatic n-alkanols are structurally very similar they might have an immunological impact that mirrors their anesthetic potency. We report the impact of the homologous C1-C12 alcohol series on the ability of activated primary human lymphocytes to produce IFN-γ. Methanol enhanced IFN-γ production whereas C2-C10 alcohols reduced the release of this cytokine. The activity of the n-alkanol series was observed within a wide concentration window ranging from millimolar levels for short chain alcohols to micromolar amounts for C7-C10 alcohols. There was a clear correlation between immunomodulatory activity and hydrophobicity of the compounds, but a cutoff effect was evident at C11. n-Alkanols were shown to act downstream of the cell membrane because T cell receptor early signaling was preserved. The activation of the nuclear factor of activated T cells (NFAT) was down-regulated progressively in accordance to the size of the n-alkanol aliphatic chains with a clear downward trend that was interrupted at C11. The nuclear factor-κB (NF-κB) signaling was also compromised, but the cutoff appeared earlier at C10. The pattern of immunomodulation and transcriptional dysregulation induced by the n-alkanol series suggested the existence of interaction pockets of defined dimensions within intracellular targets that compromise the activation of NFAT and NF-κB transcription factors and ultimately modulate the effector function of the T lymphocyte.
直链脂肪族 n- 醇是一类普遍存在的物质，根据其疏水性的不同表现出一般的麻醉特性。此外，其成员之一乙醇的免疫调节活性早已被人们所认识。我们推断，由于直链脂肪族 n- 醇的结构非常相似，它们可能具有与其麻醉效力相类似的免疫影响。我们报告了同系的 C1-C12 醇系列对激活的原代人淋巴细胞产生 IFN-γ 的能力的影响。甲醇增强了 IFN-γ 的产生，而 C2-C10 醇则减少了这种细胞因子的释放。n- 醇系列的活性在一个广泛的浓度窗口内观察到，从短链醇的毫摩尔水平到 C7-C10 醇的微摩尔水平。化合物的免疫调节活性和疏水性之间存在明显的相关性，但在 C11 处存在明显的截止效应。n- 醇被证明作用于细胞膜的下游，因为 T 细胞受体的早期信号被保留。核因子活化 T 细胞（NFAT）的激活被逐步下调，与 n- 醇脂肪族链的大小成正比，在 C11 处出现明显的下降趋势。核因子-κB（NF-κB）信号也受到损害，但在 C10 处较早出现截止。n- 醇系列诱导的免疫调节和转录失调模式表明，在细胞内靶标中存在具有特定尺寸的相互作用口袋，这些口袋会损害 NFAT 和 NF-κB 转录因子的激活，从而最终调节 T 淋巴细胞的效应功能。
