S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation
S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation
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DOI：
10.1002/hep.22231
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发表时间：
2008-05-01
期刊：
影响因子：
13.5
通讯作者：
Lu, Shelly C.
中科院分区：
文献类型：
--
作者：
Ara, Ainhoa Iglesias;Xia, Meng;Lu, Shelly C.
我们先前表明，S - 腺苷甲硫氨酸（SAMe）及其代谢产物甲基硫代腺苷（MTA）在转录水平上阻断脂多糖（LPS）诱导的RAW（小鼠巨噬细胞系）和枯否细胞中肿瘤坏死因子α（TNF - α）的表达，且不影响核因子κB的核结合。然而，这种抑制作用的确切分子机制尚不清楚。SAMe是一种甲基供体，而MTA是一种甲基化抑制剂。SAMe可自发转化为MTA，因此外源性SAMe的作用可能由MTA介导。我们目前工作的目的是检验SAMe和MTA对促炎介质的抑制作用机制是否可能涉及组蛋白甲基化的调节。在RAW细胞中，我们发现LPS通过转录和转录后机制诱导TNF - α表达。SAMe和MTA处理抑制了LPS诱导的基因转录增加。利用染色质免疫沉淀试验，我们发现LPS增加了三甲基化组蛋白3赖氨酸4（H3K4）与TNF - α启动子的结合，而这种结合被SAMe或MTA预处理完全阻断。在LPS介导的诱导型一氧化氮合酶（NOS）诱导中也观察到了类似的效应。LPS增加了组蛋白甲基转移酶Set和髓系/淋巴系白血病蛋白与这些启动子的结合，这不受SAMe或MTA的影响。MTA在RAW细胞中的作用在LPS处理的小鼠体内得到了证实。外源性SAMe不稳定，可自发转化为稳定且可透过细胞的MTA。用SAMe处理使细胞内MTA和S - 腺苷同型半胱氨酸（SAH）水平翻倍。SAH也抑制H3K4与TNF - α和NOS启动子的结合。结论：SAMe对促炎介质的药理抑制作用机制主要由MTA和SAH在组蛋白甲基化水平介导。
We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF alpha) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor kappa B nuclear binding. However, the exact molecular mechanism or mechanisms of the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may he mediated by MTA. The aim of our current work is to examine whether the mechanism of SAMe and MTA's inhibitory effect on proinflammatory mediators might involve modulation of histone methylation. In RAW cells, we found that LPS induced TNF alpha expression by both transcriptional and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the LPS-induced increase in gene transcription. Using the chromatin immunoprecipitation assay, we found that LPS increased the binding of trimethylated histone 3 lysine 4 (H3K4) to the TNF alpha promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPS-mediated induction of inducible nitric oxide synthase (NOS). LPS increased the binding of histone methyltransferases Sed and myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable and cell-permeant. Treatment with SAMe doubled intracellular MTA and S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNF alpha and NOS promoters. Conclusion: The mechanism of SAMe's pharmacologic inhibitory effect on proinflammatory mediators is mainly mediated by MTA and SAH at the level of histone methylation.