The enzyme pyrimidine 5′-nucleotidase (NT5C3A), which mediates nucleotide catabolism, was previously thought to be restricted to blood cells. We showed that expression of the gene encoding NT5C3A was induced by type I interferons (IFNs) in multiple cell types and that NT5C3A suppressed cytokine production through inhibition of the nuclear factor κB (NF-κB) pathway. NT5C3A expression required both an intronic IFN-stimulated response element and the IFN-stimulated transcription factor IRF1. Overexpression of NT5C3A, but not of its catalytic mutants, suppressed IL-8 production by HEK293 cells. Whereas knockdown of NT5C3A enhanced tumor necrosis factor (TNF)–stimulated IL-8 production, it reduced the IFN-mediated suppression of Il8 expression. Overexpression of NT5C3A increased the abundance of NAD⁺ and the activation of the sirtuins SIRT1 and SIRT6, which are NAD⁺-dependent deacetylases. NT5C3A-stimulated sirtuin activity resulted in deacetylation of histone H3 and the NF-κB subunit RelA (also known as p65), both of which were associated with the proximal region of the Il8 promoter, thus repressing the transcription of Il8. Together, these data identify an anti-inflammatory pathway that depends on the catalytic activity of NT5C3A and functions as a negative feedback regulator of inflammatory cytokine signaling.

以前认为介导核苷酸分解代谢的嘧啶5'-核苷酸酶（NT5C3A）仅限于血细胞。我们表明，在多种细胞类型中，I型干扰素（IFN）诱导了编码NT5C3A的基因的表达，并且NT5C3A通过抑制核因子κB（NF-κB）途径抑制了细胞因子的产生。NT5C3A表达需要内含子IFN刺激的响应元件和IFN刺激的转录因子IRF1。NT5C3A的过表达，而不是其催化突变体的过表达，抑制了HEK293细胞产生IL-8。敲低NT5C3A增强了肿瘤坏死因子（TNF）刺激的IL-8产生，但它减少了IFN介导的Il8表达抑制。过表达NT5C3A增加了NAD ⁺的丰度，并激活了沉默调节蛋白SIRT1和SIRT6（它们是NAD ⁺依赖性脱乙酰基酶）的激活。NT5C3A刺激的sirtuin活性导致组蛋白H3和NF-κB亚基RelA（也称为p65）脱乙酰化，二者均与Il8启动子的近端区域相关，从而抑制了Il8的转录。总之，这些数据确定了一种抗炎途径，该途径取决于NT5C3A的催化活性，并起炎性细胞因子信号传导的负反馈调节剂的作用。