Brighton & Sussex Medical School, Trafford Centre , Brighton , UK.
Free Radic Res. 2019 Aug;53(8):875-881. doi: 10.1080/10715762.2019.1637863. Epub 2019 Jul 30.
Peroxiredoxin 1 (PRDX1) is an antioxidant enzyme that, when secreted, can act as a proinflammatory signal. Here we studied the regulation of intracellular PRDX1 by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) in the RAW 264.7 mouse macrophage cell line. While LPS or IFN-γ alone did not affect PRDX1 protein levels, their combination led to an almost complete loss of the PRDX1 dimer. This was likely mediated by the increased production of nitric oxide (NO) as it was reversed by the NO synthase inhibitor L--methylarginine (L-NMMA), while a NO-releasing agent decreased PRDX1 levels. Inhibition of the proteasome with MG132 also prevented the loss of the PRDX1 dimer, suggesting that the decrease is due to a NO-activated proteasomal degradation pathway. By contrast with the decrease in protein levels, LPS increased PRDX1 mRNA and this effect was amplified by IFN-γ. Two other Nrf2 target genes, thioredoxin reductase (TXNRD1) and haem oxygenase (HMOX1), were also induced by LPS but IFN-γ did not increase their expression further. This study shows that inflammation differentially regulates PRDX1 at the levels of protein stability and gene expression, and that NO plays a key role in this mechanism.
过氧化物酶 1（PRDX1）是一种抗氧化酶，当它被分泌时，可以作为一种促炎信号。在这里，我们研究了脂多糖（LPS）和干扰素-γ（IFN-γ）在 RAW 264.7 小鼠巨噬细胞系中对细胞内 PRDX1 的调节。虽然单独的 LPS 或 IFN-γ 不会影响 PRDX1 蛋白水平，但它们的组合导致 PRDX1 二聚体几乎完全丢失。这可能是由一氧化氮（NO）的产生增加介导的，因为它被一氧化氮合酶抑制剂 L--甲基精氨酸（L-NMMA）逆转，而一种释放 NO 的试剂降低了 PRDX1 水平。用 MG132 抑制蛋白酶体也阻止了 PRDX1 二聚体的丢失，表明减少是由于 NO 激活的蛋白酶体降解途径。与蛋白水平的下降相反，LPS 增加了 PRDX1 mRNA，IFN-γ 进一步放大了这种效应。另外两个 Nrf2 靶基因，硫氧还蛋白还原酶（TXNRD1）和血红素加氧酶（HMOX1）也被 LPS 诱导，但 IFN-γ 没有进一步增加它们的表达。这项研究表明，炎症在蛋白稳定性和基因表达水平上对 PRDX1 进行了不同的调节，而 NO 在这一机制中发挥了关键作用。
