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Article 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.
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| http://dx.doi.org/10.1007/s00408-025-00787-6 | DOI Listing |
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