Lohninger Lilian, Tomasova Lenka, Praschberger Monika, Hintersteininger Michael, Erker Thomas, Gmeiner Bernhard M K, Laggner Hilde
Center of Pathobiochemistry and Genetics, Department of Medical Chemistry and Pathobiochemistry, Medical University of Vienna, Vienna, Austria.
Center of Pathobiochemistry and Genetics, Department of Medical Chemistry and Pathobiochemistry, Medical University of Vienna, Vienna, Austria; Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic; Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Biochimie. 2015 May;112:187-95. doi: 10.1016/j.biochi.2015.03.009. Epub 2015 Mar 18.
The transcription factor HIF-1α regulates the adaptive response of cells to hypoxia and oxidative stress. In addition, an important regulatory role for HIF-1α in immune reactions and inflammation is suggested. The present study attempts to investigate the effect of the gaseous signalling molecule hydrogen sulphide (H2S) on HIF-1α in THP-1 macrophages using the slow H2S releasing donor GYY4137. We found that H2S induced HIF-1α protein accumulation in THP-1 macrophages in a concentration-dependent manner. Western blot analysis of cell fractions showed that HIF-1α protein translocates into the nucleus and leads to an increase of its target protein glucose transporter-1 (GLUT-1). Activation of nuclear factor-κB (NF-κB), as well as secretion of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were reduced in the presence of H2S. These findings indicate that HIF-1α accumulation due to H2S was not triggered by the NF-κB pathway. The antioxidant pathway Nrf2/HO-1 (nuclear factor erythroid 2-related factor 2/heme oxygenase-1) was activated by H2S. Inhibition of the p38 mitogen-activated protein kinase (MAPK) reversed H2S mediated effects, suggesting that the p38 MAPK pathway may be involved in H2S induced HIF-1α/Nrf2 signalling pathways.
转录因子HIF-1α调节细胞对缺氧和氧化应激的适应性反应。此外，有研究表明HIF-1α在免疫反应和炎症中起重要调节作用。本研究试图使用缓慢释放H2S的供体GYY4137来研究气态信号分子硫化氢（H2S）对THP-1巨噬细胞中HIF-1α的影响。我们发现H2S以浓度依赖性方式诱导THP-1巨噬细胞中HIF-1α蛋白积累。细胞组分的蛋白质印迹分析表明，HIF-1α蛋白易位到细胞核中，并导致其靶蛋白葡萄糖转运蛋白-1（GLUT-1）增加。在存在H2S的情况下，核因子κB（NF-κB）的激活以及促炎细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的分泌减少。这些发现表明，H2S导致的HIF-1α积累不是由NF-κB途径触发的。抗氧化途径Nrf2/HO-1（核因子红细胞2相关因子2/血红素加氧酶-1）被H2S激活。抑制p38丝裂原活化蛋白激酶（MAPK）可逆转H2S介导的效应，这表明p38 MAPK途径可能参与H2S诱导的HIF-1α/Nrf2信号通路。
