HMGB1-RAGE signaling pathway in pPROM

Taiwan J Obstet Gynecol. 2018 Apr;57(2):211-216. doi: 10.1016/j.tjog.2018.02.008.

Abstract

Objective: Increased inflammation of the placenta is considered as a risk factor and a promoter of preterm premature rupture of the membranes (pPROM). High-mobility group box 1 (HMGB1) is a recently identified inflammatory cytokine, and HMGB1-RAGE signaling pathway has been associated with many pathophysiological processes. This study aims to reveal the mechanisms of HMGB1-RAGE signaling pathway in pPROM.

Materials and methods: The mRNA levels of relative gene of HMGB1 pathway, HMGB1, RAGE, NF-κBp65, MMP-9 and MMP-2, were analyzed by real-time PCR in placentas collected from 60 normal term women, 60 women with PROM and 60 women with pPROM. Additionally, levels of HMGB1, RAGE, NF-κBp65, MMP-9 and MMP-2 protein were detected in frozen placental specimens by western blot, and the locations of HMGB1, RAGE and NF-κBp65 were evaluated in the well-characterized tissue microarray (TMA) by immunohistochemistry. ELISA was further used to detect HMGB1, RAGE, NF-κBp65, MMP-9 and MMP-2 level in maternal and cord serum.

Results: Compared with normal term and PROM women, we found that (1) The mRNA expressions of HMGB1, RAGE, NF-κBp65, MMP-9 and MMP-2 in HMGB1-RAGE pathway of pPROM placentas were higher. (2) The protein levels of HMGB1, RAGE, NF-κBp65, MMP-9 and MMP-2 in pPROM placentas were higher. (3) HMGB1 and RAGE immunoreactivity in pPROM placenta TMA were increased in the cytoplasm of syncytiotrophoblast (STB), extravillous trophoblast (EVT) and mesenchymal cells, while NF-κBp65 was enhanced in the nucleus of STB and EVT. (4) Maternal serum concentrations of HMGB1, RAGE, NF-κBp65, MMP-9 and MMP-2 in pPROM group were greater. (5) Cord serum concentrations of HMGB1, RAGE, NF-κBp65, MMP-9 and MMP-2 among the 3 groups had no significant differences.

Conclusion: HMGB1 nuclear-cytoplasmic translocation in pPROM placenta may lead to the binding of HMGB1 to its receptor RAGE, resulting in provoking NF-κBp65 activity, and then inducing the release of MMP-9 and MMP-2, which all above activities contributed to the process of pPROM. Consequently, HMGB1-RAGE signaling pathway may be involved in the pathogenesis of pPROM.

Keywords: HMGB1; NF-κBp65; Preterm premature rupture of the membranes; RAGE.

MeSH terms

  • Adult
  • Biomarkers / blood
  • Female
  • Fetal Blood / chemistry
  • Fetal Membranes, Premature Rupture / etiology
  • Fetal Membranes, Premature Rupture / metabolism*
  • Gene Expression
  • HMGB1 Protein / blood
  • HMGB1 Protein / genetics
  • HMGB1 Protein / physiology*
  • Humans
  • Matrix Metalloproteinase 2 / analysis
  • Matrix Metalloproteinase 2 / blood
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 9 / analysis
  • Matrix Metalloproteinase 9 / blood
  • Matrix Metalloproteinase 9 / genetics
  • NF-kappa B / analysis
  • NF-kappa B / blood
  • NF-kappa B / genetics
  • Placenta / chemistry
  • Pregnancy
  • RNA, Messenger / analysis
  • Receptor for Advanced Glycation End Products / blood
  • Receptor for Advanced Glycation End Products / genetics
  • Receptor for Advanced Glycation End Products / physiology*
  • Signal Transduction / physiology*

Substances

  • AGER protein, human
  • Biomarkers
  • HMGB1 Protein
  • NF-kappa B
  • RNA, Messenger
  • Receptor for Advanced Glycation End Products
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9

Supplementary concepts

  • Preterm Premature Rupture of the Membranes