新發(fā)現(xiàn)：琥珀酸炎癥信號通路信息

【資料簡介】

由革蘭氏陰性細菌產(chǎn)物脂多糖激活的巨噬細胞，核心代謝從氧化磷酸化轉(zhuǎn)化至糖酵解。近日一個研究小組一項成果表明，小鼠巨噬細胞中，2-脫氧葡萄糖對糖酵解的抑制，抑制了脂多糖誘導(dǎo)的白細胞介素-1β（IL-1β），而非腫瘤壞死因子α（TNF-α）。相關(guān)研究論文于2013年3月24日在線發(fā)表在Nature雜志上。

脂多糖激活的巨噬細胞完整代謝圖表明，糖酵解基因表達上調(diào)，線粒體基因表達下調(diào)，這和代謝產(chǎn)物表達譜相關(guān)。脂多糖增加了三羧酸循環(huán)中琥珀酸（succinate）的水平。依賴回補反應(yīng)（anerplerosis）是琥珀酸的主要來源，盡管‘GABA （γ-aminobutyric acid） shunt’ 也發(fā)揮一定作用。

脂多糖誘導(dǎo)琥珀酸穩(wěn)定了缺氧誘導(dǎo)因子-1 ，以IL-1β為靶標，可被2-脫氧葡萄糖抑制。脂多糖也增加的幾種蛋白質(zhì)的琥珀酰化。因此，研究人員確定琥珀酸是先天免疫信號的代謝物，應(yīng)對炎癥過程時，它可以提高白細胞介素-1β的產(chǎn)量

原文摘要：

Succinate is an inflammatory signal that induces IL-1β through HIF-1α

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis1. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the ‘GABA （γ-aminobutyric acid） shunt’ pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β