title: 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.
abstract: 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.
authors.affiliation: Department of Immunology and Key Laboratory of Molecular Medicine of Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Zheng
authors.forename: Naixiang
authors.initials: N
authors.lastname: Luo
authors.forename: Dongzhen
authors.initials: D
authors.lastname: Mu
authors.forename: Pei
authors.initials: P
authors.lastname: Jiang
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.forename: Haozhe
authors.initials: H
authors.lastname: Sun
authors.forename: Shudao
authors.initials: S
authors.lastname: Xiong
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.forename: Luman
authors.initials: L
authors.lastname: Wang
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
mesh_terms: D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide