Hydrogen Sulfide Contributes to Uterine Quiescence Through Inhibition of NLRP3 Inflammasome Activation by Suppressing the TLR4/NF-κB Signalling Pathway

Chen, Zixi; Zhang, Mengzhe; Zhao, Yunzhi; Xu, Wenjuan; Xiang, Fenfen; Li, Xiaoxiao; Zhang, Tao; Wu, Rong; Kang, Xin

doi:10.2147/jir.s308558

Cited by 19 publications

(12 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several in vitro studies have shown that during pregnancy the production of H 2 S by the uterine vascular smooth cells is increased and this facilitates uterine quiescence 23,24 . Other mouse studies of PTD induced by LPS have shown that H 2 S acts as a counter anti‐inflammatory mechanism which inhibits NLRP3‐inflammasome activation and the subsequent cleavage of pro‐IL‐1β to the active IL‐1β moiety 14,25 . In these studies the role of endogenous H 2 S production through gene knock‐outing has not been studied; retardation of PTD was achieved through the administration of the H 2 S donor sodium sulfate.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of hydrogen sulfide production and pregnancy rate in an experimental model: Association with preterm delivery

Panagiotopoulos

Andriopoulou

Spanou

et al. 2023

American J Rep Immunol

View full text Add to dashboard Cite

ProblemPro‐inflammatory phenomena drive preterm delivery (PTD). Hydrogen sulfide is a gasotransmitter with anti‐inflammatory properties produced through the activity of the enzyme cystathionine‐γ‐lyase (CSE), and its impact was studied in models of normal delivery and PTD in mice.Method of studyFemale CSE+/+ and CSE−/− mice were mated with male CSE+/+ mice; mating was done with drinking water unsupplemented and supplemented with cysteine. The pregnancy rate was monitored. PTD was induced by the intraperitoneal injection of bacterial lipopolysaccharide (LPS) on day 14.5 of pregnancy. Mice were sacrificed for tissue collection and splenocyte isolation after 6 and 12 h. Isolated splenocytes were stimulated for the production of tumor necrosis factor‐alpha (TNFα), interleukin (IL)‐10 and interferon‐gamma (IFNγ); TNFα and vascular endothelial growth factor (VEGF) were measured in the fetuses and the placenta.ResultsThe successful pregnancy rate was lower in CSE−/− mice and it was restored with cysteine supplementation. CSE deficiency was associated with higher tissue concentrations of TNFα in the fetuses, attenuated IL‐10 responses and higher IFNγ production from splenocytes. CSE deficiency was not associated with PTD. Following PTD induction, CSE−/− mice did not show attenuated IL‐10 responses but the production of TNFα and IFNγ was lowered over‐time; placental VEGF was also increased over‐time.ConclusionsCSE deficiency has an unfavorable impact on pregnancy. H2S deficiency through CSE does not drive PTD but mediates pro‐inflammatory phenomena in fetuses.

show abstract

Section: Discussionmentioning

confidence: 99%

Deficiency of hydrogen sulfide production and pregnancy rate in an experimental model: Association with preterm delivery

Panagiotopoulos

Andriopoulou

Spanou

et al. 2023

American J Rep Immunol

View full text Add to dashboard Cite

show abstract

“…HMSMCs were isolated from TNL myometrial tissues following the previously described protocol ( 29 ). In brief, myometrial tissue pieces were incubated with DMEM supplemented with 1 mg/mL collagenase type II (Invitrogen) and 1 mg/mL deoxyribonuclease I at 37°C with shaking for 30 min, repeated twice.…”

Section: Methodsmentioning

confidence: 99%

Elevated expression of Toll-like receptor 4 and cytokines in both serum and myometrium at term may serve as promising biomarkers for uterine activation preceding labor

Chen,

Li,

et al. 2023

Front. Endocrinol.

Self Cite

View full text Add to dashboard Cite

ObjectiveIncreased inflammation and cytokine levels are considered risk factors and promoters of preterm birth (PTB). However, the regulatory mechanism of pregnancy-related inflammation remains unclear. Toll-like receptor 4 (TLR4) plays a critical role in inflammatory responses in various diseases. Therefore, our study aimed to investigate whether TLR4 is involved in the inflammatory responses during uterine activation for labor, with the goal of identifying potential biomarkers for uterine activation at term.Materials and methodsWe used flow cytometry to detect TLR4 expression on CD14+ maternal blood monocytes in the first, second, and third trimesters. ELISA was employed to measure TLR4 and cytokines levels in the maternal serum of term non-labor (TNL), term labor (TL) women and LPS induced preterm labor and PBS injected controls. TLR4siRNA was transfected into the human myometrial smooth muscle cells (HMSMCs), which were subsequently treated with IL-1β. The mRNA and protein levels of TLR4, uterine contraction-related protein connexin 43 (CX43), oxytocin receptor (OTR), MAPK/NF-κB signaling pathway, and cytokines were analyzed using qRT-PCR, western blotting, and immunohistochemistry.ResultsThe study revealed TLR4 expression on CD14+ maternal blood monocytes was higher in the third trimester group compared to the first and second trimester groups (p<0.001). Maternal serum concentrations of TLR4 and cytokines were significantly higher in the TL group than the TNL group (p<0.001). TLR4, OTR, CX43, activated MAPK/NF-κB expression, and cytokines levels were upregulated in TL group, and similarly significantly higher in the LPS-induced preterm group than in the control group. Using the HMSMCs we demonstrated that TLR4siRNA transfection suppressed contractility. Interfering with TLR4 expression reduced the expression of OTR, CX43, cytokines, and MAPK/NF-κB activation. There was a significant positive relationship between TLR4 expression and the inflammatory status in the myometrium. ROC analysis indicated that TLR4 and cytokines may serve as potential biomarkers for predicting uterine activation for labor.ConclusionOur data suggest that TLR4 and cytokines can act as stimulators of uterine activation for labor at term. Furthermore, the MAPK/NF-κB pathway appears to be one of the potential signaling pathways mediating TLR4’s regulation of parturition initiation.

show abstract

“…The nitric oxide metabolites S-nitrosoglutathione (GSNO) and peroxynitrite (ONOOÀ) mediate S-nitrosation and cytotoxicity, respectively, to promote uterine relaxation and cervical remodeling. 56 Another gasotransmitter, hydrogen sulfide, inhibits the expression of contraction associated protein genes (Connexin 43 (CX-43), PTGFR, oxytocin receptor (OTR)) to suppress spontaneous contraction of the human uterus 57 and reverses the lipopolysaccharides (LPS)induced PTL by its anti-inflammatory effects. 58 Mammalian microRNAs (miRNA/miR) play especially powerful roles in smooth muscle cells and in female reproduction, wherein they have been implicated in hormone responsiveness.…”

Section: Cervical and Myometrium Modification And Remodelingmentioning

confidence: 99%

Preterm Labor, a Syndrome Attributed to the Combination of External and Internal Factors

Liu

2021

Maternal-Fetal Medicine

View full text Add to dashboard Cite

Preterm labor (before 37 weeks' gestation) is the leading cause of neonatal mortality and morbidity, which can be divided into iatrogenic preterm labor, infectious preterm labor, and spontaneous preterm labor (sPTL). Up to now, there continue to be great difficulties in prediction and prevention of sPTL, owing to multiple risk factors, pathogenesis, and pathologic processes contributing to the event, which have not been fully clarified. Pregnancy maintenance and parturition is a complicated process with continuous maternal-fetal dialogue, in which both maternal and fetal factors participate and affect the outcome of pregnancy, including sPTL. Besides, external factors can also participate in sPTL, individually or through the interaction with internal factors. In this article, we summarize recent studies regarding sPTL from our and other groups, and discuss the risk factors and pathogenesis of preterm birth from both external and internal (maternal and fetal) aspects, so as to provide theoretical evidences for the diagnosis, prevention, and treatment of sPTL in the future.

show abstract

Hydrogen Sulfide Contributes to Uterine Quiescence Through Inhibition of NLRP3 Inflammasome Activation by Suppressing the TLR4/NF-κB Signalling Pathway

Cited by 19 publications

References 45 publications

Deficiency of hydrogen sulfide production and pregnancy rate in an experimental model: Association with preterm delivery

Deficiency of hydrogen sulfide production and pregnancy rate in an experimental model: Association with preterm delivery

Elevated expression of Toll-like receptor 4 and cytokines in both serum and myometrium at term may serve as promising biomarkers for uterine activation preceding labor

Preterm Labor, a Syndrome Attributed to the Combination of External and Internal Factors

Contact Info

Product

Resources

About