Vascular inflammaging: Endothelial CEACAM1 expression is upregulated by TNF‐α via independent activation of NF‐κB and β‐catenin signaling

Abstract Chronic inflammation with progressive age, called inflammaging, contributes to the pathogenesis of cardiovascular diseases. Previously, we have shown increased vascular expression of the Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) in aged mice and humans, presumably via mutual upregulation with the pro‐inflammatory cytokine TNF‐α. CEACAM1 is critical for aging‐associated vascular alterations like endothelial dysfunction, fibrosis, oxidative stress, and sustained inflammation and can be regarded as a main contributor to vascular inflammaging. This study was conducted to elucidate the mechanisms underlying endothelial CEACAM1 upregulation by TNF‐α in detail. Using wildtype (WT) and TNF‐α knockout ( Tnf − /− ) mice, we confirmed that the aging‐related upregulation of endothelial CEACAM1 critically depends on TNF‐α. The underlying mechanisms were analyzed in an endothelial cell culture model. TNF‐α time‐dependently upregulated CEACAM1 in vitro. In pharmacological experiments, we identified an early NF‐κB‐ and a delayed β‐catenin‐mediated response. Involvement of β‐catenin was further substantiated by siRNA‐mediated knockdown of the β‐catenin‐targeted transcription factor TCF4. Both signaling pathways acted independent from each other. Elucidating the delayed response, co‐immunoprecipitation analysis revealed release of β‐catenin from adherens junctions by TNF‐α. Finally, TNF‐α activated Akt kinase by increasing its Ser 473 phosphorylation. Consequently, Akt kinase facilitated β‐catenin signaling by inhibiting its degradation via phosphorylation of GSK3β at Ser 9 and by increased phosphorylation of β‐catenin at Ser 552 that augments its transcriptional activity. Taken together, our study provides novel mechanistic insights into the aging‐related, inflammation‐mediated endothelial upregulation of CEACAM1. Beyond the pathogenesis of cardiovascular diseases, these findings may be significant to all fields of inflammaging.