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Lipopolysaccharide regulates biosynthesis of cystathionine γ-lyase and hydrogen sulfide through toll-like receptor-4/p38 and toll-like receptor-4/NF-κB pathways in macrophages
- Zheng, Yijie, Luo, Naixiang, Mu, Dongzhen, Jiang, Pei, Liu, Ronghua, Sun, Haozhe, Xiong, Shudao, Liu, Xiaoming, Wang, Luman, Chu, Yiwei
- In vitro cellular & developmental biology 2013 v.49 no.9 pp. 679-688
- biosynthesis, cystathionine gamma-lyase, hydrogen sulfide, inflammation, lipopolysaccharides, macrophages, mice, mitogen-activated protein kinase
- Hydrogen sulfide (H₂S), formed mainly by the enzyme cystathionine γ-lyase (CSE) in macrophages, is emerging as a novel regulator in inflammation. Although elevated production of H₂S has been shown in inflammatory processes, the underlying molecular mechanism remains to be further elucidated. In this study, we compared parallel TLR4 knockout (TLR4⁻/⁻) mice with their wild-type counterparts following lipopolysaccharide (LPS) treatment. It showed that LPS increased the expressions of CSE and biosynthesis of H₂S in C57BL/6 mice both in vivo and in vitro. However, the effects of LPS were not present in TLR4⁻/⁻ mice, indicating the crucial role of TLR4 in LPS-induced expression of CSE and biosynthesis of H₂S. We subsequently used JNK inhibitor, P38 inhibitor, and ERK inhibitor to block the downstream MAPK pathways of TLR4 in macrophages, and found that LPS-induced CSE expression and H₂S synthesizing activity were inhibited by pretreatment with the p38 inhibitor. Similarly, the NF-κB inhibitor (BAY 11-7082) reversed the effects of LPS. These results suggest that LPS increases the biosynthesis of CSE and H₂S in macrophages mainly in a TLR4-p38-dependent and TLR-4-NF-κB-dependent manner. These findings expand our knowledge of H₂S biosynthesis during inflammation and provide a foundation for the development of novel H₂S-based therapies.