2. Academic Validation
  3. PDE4B Modulates Phosphorylation of p65 (Ser468) via cAMP/PKA in Acute Lung Injury

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

  • Lung. 2025 Feb 16;203(1):33. doi: 10.1007/s00408-025-00787-6.
Rana Dhar # 1 2,  Yajun Li # 3,  Zhengqiang Hu # 1,  Shunde Song # 1,  Zhewen Zhang 1,  Jie Ji 1,  Xuefeng Wang 4,  Xuyang Zheng 5,  Zigang Li 6,  Chunguang Yan 7,  Huifang Tang 8 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
  • 2 Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, and Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310016, Zhejiang, China.
  • 3 Department of Pharmacy, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410008, China.
  • 4 Department of Pharmacy, Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310005, Zhejiang, China.
  • 5 Department of Pediatrics, The Affiliated Hangzhou First People's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, China.
  • 6 Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China.
  • 7 Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing, 210009, China. ycgagcy@163.com.
  • 8 Department of Pharmacology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang, China. tanghuifang@zju.edu.cn.
  • 9 Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, and Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310016, Zhejiang, China. tanghuifang@zju.edu.cn.
  • # Contributed equally.
PMID: 39956855 DOI: 10.1007/s00408-025-00787-6
Abstract

Aim: The important role of phosphodiesterase 4B (PDE4B) inhibition on lipopolysaccharide (LPS)-induced ALI has been reported. However, the corresponding mechanisms remain unclear. In the present study, the relationship between PDE4B and phosphorylation of p65 (Ser468) in LPS-induced injury by in vivo and in vitro models was investigated.

Methods and results: pde4b+/+ mice, inflammation was significantly up-regulated after LPS stimulation, including the highest number of immune cells, especially neutrophils, and the level of pro-inflammatory cytokines measured by ELISA, while all those were blunted in pde4b-/- mice. Moreover, pde4b-/- mice improved the expression of PKA in lung tissues and down-regulated the IKKα/β-NF-κB p65 signaling determined by western blotting. In vitro experiments in MH-S cells revealed that siRNA-mediated specific silence of PDE4B expression resulted in a decrease of inflammatory markers and phosphorylation of p65 at Ser468 after LPS treatment, but overexpressing PDE4B increased the inflammation and phosphorylation of p65 at Ser468. In MH-S cells, luciferase analysis indicated that PDE4B acts as a positive regulator of p65 in inflammation. PKA Inhibitor (H-89) increased pP65 and PDE4B expression, while PKA Activator (6-BZ-cAMP) showed the opposite effect in macrophages. More importantly, the proteasome-mediated degradation of cAMP effector was negatively correlated with the phosphorylation of p65 (Ser468) and PDE4B expression in MH-S cells.

Conclusions: PDE4B plays a critical role in orchestrating LPS-induced acute lung inflammation by cAMP/PKA axis-mediated phosphorylation of p65.

Keywords

Acute lung injury; Macrophage; PDE4B; PKA; p65.

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