Prostaglandin E2 alleviates inflammatory response and lung injury through EP4/cAMP/IKK/NF-κB pathway

  • Biochim Biophys Acta Mol Basis Dis. 2025 Mar 14;1871(5):167801. doi: 10.1016/j.bbadis.2025.167801.
Yelin Tang  1 ,  Weiting Pan  2 ,  Wenting Ding  2 ,  Xingye Pan  3 ,  Junyi Zhu  2 ,  Huiwen Chen  2 ,  Xiaona Zhu  4 ,  Jingyi Chen  2 ,  Zijun Cheng  2 ,  Yali Zhang  5 ,  Bing Zhang  6
Affiliations
  • 1. Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Guangdong Food and Drug Vocational College, Guangzhou, Guangdong 510520, China.
  • 2. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3. The First Affiliated Medical College of Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 4. Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China.
  • 5. Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 6. Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325600, China. Electronic address: [email protected].
PMID: 40090625 DOI: 10.1016/j.bbadis.2025.167801
Abstract

Purpose: Prostaglandin E2 (PGE2), a pivotal lipid metabolite, plays a dual role in inflammation, manifesting both pro-inflammatory and anti-inflammatory effects, which are significantly influenced by the cellular microenvironment and receptor subtype. Although recent studies have highlighted the anti-inflammatory potential of PGE2, its role in Toll-like Receptor (TLR)-associated inflammation and the underlying mechanisms have not fully elucidated. Consequently, the primary aim of this study was to assess the anti-inflammatory efficacy of PGE2 in TLR-related inflammation and to elucidate the associated mechanisms.

Methods: In vitro, the anti-inflammatory effect of PGE2 on TLR-related inflammation were investigated by measuring pro-inflammatory cytokine protein and gene levels using ELISA and RT-qPCR, respectively. Western blot analysis was used to explore the corresponding anti-inflammatory signaling pathways. In vivo, the anti-inflammatory effects of PGE2 were further validated using ALI and sepsis models, employing the PGE2 analog 16,16-dimethyl prostaglandin E2 (dmPGE2).

Results: The findings revealed that PGE2 inhibited the LPS-induced inflammatory response and activation of the IKK/NF-κB signaling pathway via the EP4 receptor-mediated downstream cAMP/PKA pathway. Additionally, PGE2 analog, dmPGE2, effectively mitigated pathological injury and the inflammatory response in lung tissue of mice subjected to LPS-induced ALI and sepsis. Notably, dmPGE2 suppressed LPS-induced activation of the IKK/NF-κB signaling pathway in lung tissue.

Conclusion: This study demonstrated that PGE2 can inhibit the IKK/NF-κB signaling pathway through the EP4/cAMP/PKA pathway, thereby alleviating the LPS-induced inflammatory response and providing a protective effect against LPS-induced ALI and sepsis. Consequently, PGE2 holds promise as a candidate for drug development aimed at preventing ALI and sepsis.

Keywords
Acute lung injury; Lipopolysaccharide; NF-κB; Prostaglandin E2; Sepsis.
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