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.

Inhibition of Hydrogen Sulfide Production by Gene Silencing Attenuates Inflammatory Activity by Downregulation of NF-κB and MAP Kinase Activity in LPS-Activated RAW 264.7 Cells

“…Recently, NF- κ B has been shown to be involved in TLR4-mediated upregulation of CSE mRNA expression and generation of hydrogen sulfide in LPS-induced macrophages [36]. In accordance with this report, our findings also suggest that NF- κ B plays a key role in the inflammatory response of LPS-induced macrophages.…”

“…Phosphorylation of ERK increased as early as 15 min after LPS treatment and reached a peak at 30 min which was in accordance with previous reports [35, 36]. However, it is of interest to note that inhibition of hydrogen sulfide production by silencing the CSE gene using siRNA in cells treated with LPS for 30 min resulted in reduced phosphorylation of ERK.…”

TLR2 and TLR4 interact with sulfide system in the modulation of mouse colonic motility

“…Interestingly, and in relation to previous studies showing a relationship between H 2 S and TLR4, activation with LPS induces an increase in CSE expression and the free sulfide levels in colon, resulting in an increase of the motor response induced by PAG. Other studies have shown that the activation of TLR4 by LPS increases the biosynthesis of CSE and H 2 S in mouse macrophages through p38/MAPKs and NF‐κB signaling . On the contrary, LPS decreased CSE expression in human endothelial cells and blocked H 2 S production in mouse aorta tissues .…”

Broad-Range Antiviral Activity of Hydrogen Sulfide Against Highly Pathogenic RNA Viruses

“…46). For example, GYY4137-associated inhibition of LPS-induced macrophage activation and bleomycin-induced pulmonary fibrosis was dependent on decreased NF-κB induction4748. Transcription factors belonging to the IRF and NF-κB families play a significant role in the pathogenesis of influenza A virus infections by mounting an inflammatory response through TLR3 and RIG-I activation by viral RNA1927, similar to other viruses including paramyxoviruses49505152.…”