Background

Hydrogen sulfide donors reduce inflammatory signaling in vitro and in vivo. The biological effect mediated by H₂S donors depends on the kinetics of the gas release from the donor molecule. However, the molecular mechanisms of H₂S-induced immunomodulation were poorly addressed. Here, we studied the effect of two different hydrogen sulfide (H₂S)-producing agents on the generation of the LPS-induced inflammatory mediators. Importantly, we investigated the transcriptomic changes that take place in human cells after the LPS challenge, combined with the pretreatment with a slow-releasing H₂S donor-GYY4137.

Methods

We investigated the effects of GYY4137 and sodium hydrosulfide on the release of proinflammatory molecules such as ROS, NO and TNF-α from LPS-treated human SH-SY5Y neuroblastoma and the THP-1 promonocytic cell lines. Transcriptomic and RT-qPCR studies using THP-1 cells were performed to monitor the effects of the GYY4137 on multiple signaling pathways, including various immune-related and proinflammatory genes after combined action of LPS and GYY4137.

Results

The GYY4137 and sodium hydrosulfide differed in the ability to reduce the production of the LPS-evoked proinflammatory mediators. The pre-treatment with GYY4137 resulted in a drastic down-regulation of many TNF-α effectors that are induced by LPS treatment in THP-1 cells. Furthermore, GYY4137 pretreatment of LPS-exposed cells ameliorates the LPS-mediated induction of multiple pro-inflammatory genes and decreases expression of immunoproteasome genes. Besides, in these experiments we detected the up-regulation of several important pathways that are inhibited by LPS.

Conclusion

Based on the obtained results we believe that our transcriptomic analysis significantly contributes to the understanding of the molecular mechanisms of anti-inflammatory and cytoprotective activity of hydrogen sulfide donors, and highlights their potential against LPS challenges and other forms of inflammation.

中文翻译：

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H 2 S通过调节人类细胞中的多种途径来抵消LPS的促炎作用

背景

硫化氢供体在体外和体内减少炎症信号。H ₂ S供体介导的生物学效应取决于从供体分子释放气体的动力学。但是，H ₂ S诱导的免疫调节的分子机制尚未明确。在这里，我们研究了两种不同的硫化氢（H ₂ S）产生剂对LPS诱导的炎症介质产生的影响。重要的是，我们调查了LPS攻击后在人类细胞中发生的转录组变化，并结合了缓慢释放的H ₂ S供体-GYY4137进行的预处理。

方法

我们研究了GYY4137和硫化氢钠对LPS处理的人SH-SY5Y神经母细胞瘤和THP-1单核细胞系中促炎分子如ROS，NO和TNF-α释放的影响。进行了使用THP-1细胞的转录组和RT-qPCR研究，以监测GYY4137对LPS和GYY4137共同作用后对多种信号通路的影响，包括各种免疫相关基因和促炎基因。

结果

GYY4137和氢硫化钠在减少LPS诱发的促炎性介质产生方面的能力有所不同。用GYY4137预处理导致TPS-1细胞中LPS处理诱导的许多TNF-α效应物急剧下调。此外，LPY暴露的细胞的GYY4137预处理可改善LPS介导的多种促炎基因的诱导，并降低免疫蛋白酶体基因的表达。此外，在这些实验中，我们检测到了LPS抑制的几个重要途径的上调。

结论

基于获得的结果，我们认为我们的转录组分析显着有助于理解硫化氢供体抗炎和细胞保护活性的分子机制，并突出了其对抗LPS挑战和其他形式炎症的潜力。