Dexmedetomidine activates the PKA/CREB pathway and inhibits proinflammatory factor expression through β2 adrenergic receptors

Abstract

IntroductionDexmedetomidine (DEX) is primarily utilized for sedation in the context of general anesthesia or intensive care. However, the exact regulatory mechanism by which DEX affects cytokines remains unclear. This study aims to investigate the underlying mechanism by which DEX inhibits proinflammatory factors through activation of the β2 adrenergic receptor (β2 AR).MethodsThe inflammatory cell model of human mononuclear macrophage (THP‐1) cells induced by lipopolysaccharide (LPS) was established to study the effect of DEX on the expression of cell‐related inflammatory factors. ADRA2A gene knockout THP‐1 cells (THP‐1KO) were constructed by CRISPR technology, and the effect of DEX on the expression of inflammatory factors of THP‐1KO cells was detected. The target sites of DEX on β2 AR were screened by molecular docking. Reversion experiments were performed using ADRB2‐siRNA. Western blot was used to detect the activation of β2 AR/PKA/CREB pathway and NF‐κB, and ELISA was used to detect the release level of inflammatory factors.ResultsThe results demonstrated a significant reduction in the expression levels of MCP‐1, interleukin‐06, and IL‐8 in both THP‐1 and THP‐1KO cells when induced by LPS following treatment with DEX. Additionally, DEX treatment led to an increase in IL‐10 expression. Immunofluorescence analysis revealed an upregulation of β2 AR expression after DEX treatment. Western blot results indicated that DEX notably enhanced the activation of the β2 AR and PKA/CREB pathways, while concurrently suppressing the activation of NF‐κB. Notably, the use of ADRB2 siRNA reversed the effects of DEX treatment and promoted the release of inflammatory cytokines.ConclusionDEX initiates the activation of the PKA/CREB pathway through the activation of β2 AR. Simultaneously, it exerts an inhibitory effect on the activation of NF‐κB, consequently reducing the transcription of proinflammatory factors while increasing the transcription of anti‐inflammatory factors.