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Glucocorticoids Impair the 7α-Hydroxycholesterol-Enhanced Innate Immune Response

  • Yonghae Son (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Bo-Young Kim (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Miran Kim (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Jaesung Kim (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Ryuk Jun Kwon (Family Medicine Clinic and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital) ;
  • Koanhoi Kim (Department of Pharmacology, School of Medicine, Pusan National University)
  • Received : 2023.09.05
  • Accepted : 2023.10.12
  • Published : 2023.10.31
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Abstract

Glucocorticoids suppress the vascular inflammation that occurs under hypercholesterolemia, as demonstrated in an animal model fed a high-cholesterol diet. However, the molecular mechanisms underlying these beneficial effects remain poorly understood. Because cholesterol is oxidized to form cholesterol oxides (oxysterols) that are capable of inducing inflammation, we investigated whether glucocorticoids affect the immune responses evoked by 7α-hydroxycholesterol (7αOHChol). The treatment of human THP-1 monocytic cells with dexamethasone (Dex) and prednisolone (Pdn) downregulated the expression of pattern recognition receptors (PRRs), such as TLR6 and CD14, and diminished 7αOHChol-enhanced response to FSL-1, a TLR2/6 ligand, and lipopolysaccharide, which interacts with CD14 to initiate immune responses, as determined by the reduced secretion of IL-23 and CCL2, respectively. Glucocorticoids weakened the 7αOHChol-induced production of CCL2 and CCR5 ligands, which was accompanied by decreased migration of monocytic cells and CCR5-expressing Jurkat T cells. Treatment with Dex or Pdn also reduced the phosphorylation of the Akt-1 Src, ERK1/2, and p65 subunits. These results indicate that both Dex and Pdn impair the expression of PRRs and their downstream products, chemokine production, and phosphorylation of signaling molecules. Collectively, glucocorticoids suppress the innate immune response and activation of monocytic cells to an inflammatory phenotype enhanced or induced by 7αOHChol, which may contribute to the anti-inflammatory effects in hypercholesterolemic conditions.

Keywords

Acknowledgement

This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF2019R1I1A3A01055344; K.K.), and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2022R1F1A107476911; R.J.K.).

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