Institute for Research in Biomedicine, Barcelona, Spain.
Eur J Immunol. 2012 Nov;42(11):3028-37. doi: 10.1002/eji.201242413. Epub 2012 Sep 20.
The amount of arginine available at inflammatory loci is a limiting factor for the growth of several cells of the immune system. IL-4-induced activation of macrophages produced arginase-1, which converts arginine into ornithine, a precursor of polyamines and proline. Trichostatin A (TSA), a pan-inhibitor of histone deacetylases (HDACs), inhibited IL-4-induced arginase-1 expression. TSA showed promoter-specific effects on the IL-4-responsive genes. While TSA inhibited the expression of arginase-1, fizz1, and mrc1, other genes, such as ym,1 mgl1, and mgl2, were not affected. The inhibition of arginase-1 occurred at the transcriptional level with the inhibition of polymerase II binding to the promoter. IL-4 induced STAT6 phosphorylation and binding to DNA. These activities were not affected by TSA treatment. However, TSA inhibited C/EBPβ DNA binding. This inhibitor induced acetylation on lysine residues 215-216, which are critical for DNA binding. Finally, using macrophages from STAT6 KO mice we showed that STAT6 is required for the DNA binding of C/EBPβ. These results demonstrate that the acetylation/deacetylation balance strongly influences the expression of arginase-1, a gene of alternative activation of macrophages. These findings also provide a molecular mechanism to explain the control of gene expression through deacetylase activity.
在炎症部位，精氨酸的含量是免疫系统中几种细胞生长的限制因素。IL-4 诱导巨噬细胞产生精氨酸酶-1，将精氨酸转化为鸟氨酸，鸟氨酸是多胺和脯氨酸的前体。曲古抑菌素 A（TSA），一种组蛋白去乙酰化酶（HDACs）的泛抑制剂，抑制了 IL-4 诱导的精氨酸酶-1的表达。TSA 对 IL-4 反应基因表现出启动子特异性的影响。虽然 TSA 抑制了精氨酸酶-1、fizz1 和 mrc1 的表达，但其他基因，如 ym、1 mgl1 和 mgl2，不受影响。精氨酸酶-1的抑制发生在转录水平上，聚合酶 II 与启动子的结合受到抑制。IL-4 诱导 STAT6 磷酸化并与 DNA 结合。这些活性不受 TSA 处理的影响。然而，TSA 抑制了 C/EBPβ 的 DNA 结合。这种抑制剂诱导赖氨酸残基 215-216 的乙酰化，这对于 DNA 结合是至关重要的。最后，我们使用 STAT6 KO 小鼠的巨噬细胞表明，STAT6 是 C/EBPβ 的 DNA 结合所必需的。这些结果表明，乙酰化/去乙酰化平衡强烈影响精氨酸酶-1的表达，精氨酸酶-1是巨噬细胞替代激活的一个基因。这些发现也为通过去乙酰化酶活性控制基因表达提供了一个分子机制。
