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PDE4B Modulates Phosphorylation of p65 (Ser468) via cAMP/PKA in Acute Lung Injury

Rana Dhar1,2, Yajun Li3, Zhengqiang Hu1

  • 1Department of Pharmacology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang, China.

Lung
|February 16, 2025
PubMed
Abstract

Insights

Phosphodiesterase 4B (PDE4B) inhibition reduces lipopolysaccharide (LPS)-induced acute lung inflammation (ALI). PDE4B promotes inflammation by activating the cAMP/PKA pathway, leading to p65 phosphorylation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Phosphodiesterase 4B (PDE4B) is implicated in lipopolysaccharide (LPS)-induced acute lung injury (ALI).
  • The precise mechanisms underlying PDE4B's role in ALI remain incompletely understood.
  • This study investigates the relationship between PDE4B and p65 phosphorylation in LPS-induced injury.

Purpose of the Study:

  • To elucidate the role of PDE4B in LPS-induced acute lung inflammation.
  • To investigate the molecular mechanisms involving PDE4B, cAMP/PKA signaling, and p65 phosphorylation.
  • To determine PDE4B's function as a regulator in inflammatory responses.

Main Methods:

  • In vivo studies using wild-type and PDE4B-deficient mice stimulated with LPS.
  • In vitro experiments using MH-S cells with siRNA-mediated PDE4B knockdown and overexpression.
  • Analysis of inflammatory markers, cytokine levels (ELISA), protein signaling pathways (Western blotting), and luciferase assays.

Main Results:

  • PDE4B deficiency blunted LPS-induced inflammation, reducing immune cell infiltration and pro-inflammatory cytokines in mice.
  • PDE4B deficiency improved PKA expression and downregulated IKKα/β-NF-κB p65 signaling.
  • In vitro, PDE4B knockdown decreased p65 phosphorylation (Ser468) and inflammation markers, while overexpression increased them.
  • PDE4B acts as a positive regulator of p65 in inflammation via the cAMP/PKA axis.

Conclusions:

  • PDE4B plays a critical role in orchestrating LPS-induced acute lung inflammation.
  • The cAMP/PKA axis mediates PDE4B's effect through the phosphorylation of p65.
  • Targeting PDE4B may offer a therapeutic strategy for acute lung inflammation.
Keywords:
Acute lung injuryMacrophagePDE4BPKAp65

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