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Glucocorticoids Impair the 7α-Hydroxycholesterol-Enhanced Innate Immune Response
Yonghae Son1, Bo-Young Kim1, Miran Kim1
1Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
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.
Insights
Glucocorticoids, like dexamethasone and prednisolone, reduce inflammation caused by cholesterol oxides by downregulating immune cell receptors and signaling pathways. This mechanism may explain their anti-inflammatory effects in high cholesterol conditions.
Area of Science:
- Immunology
- Endocrinology
- Molecular Biology
Background:
- Hypercholesterolemia can lead to vascular inflammation.
- Cholesterol oxides (oxysterols) are known to induce inflammatory responses.
- The anti-inflammatory mechanisms of glucocorticoids in hypercholesterolemia are not fully understood.
Purpose of the Study:
- To investigate how glucocorticoids affect immune responses to 7α-hydroxycholesterol (7αOHChol), an inflammatory oxysterol.
- To elucidate the molecular mechanisms by which glucocorticoids suppress oxysterol-induced inflammation.
Main Methods:
- Human THP-1 monocytic cells were treated with glucocorticoids (dexamethasone and prednisolone) and 7αOHChol.
- Expression of pattern recognition receptors (PRRs) like TLR6 and CD14 was analyzed.
- Cytokine (IL-23, CCL2) secretion and cell migration were measured.
- Phosphorylation of key signaling molecules (Akt-1, Src, ERK1/2, p65) was assessed.
Main Results:
- Glucocorticoids downregulated PRRs (TLR6, CD14) and diminished responses to TLR ligands (FSL-1, LPS).
- 7αOHChol-induced secretion of IL-23 and CCL2 was reduced by glucocorticoid treatment.
- Glucocorticoids decreased the production of CCL2 and CCR5 ligands, impairing monocyte and T cell migration.
- Phosphorylation of signaling proteins including Akt-1, Src, ERK1/2, and p65 was reduced.
Conclusions:
- Glucocorticoids suppress the innate immune response to 7αOHChol by downregulating PRRs and downstream signaling.
- These drugs reduce chemokine production and inflammatory cell migration.
- The findings suggest glucocorticoids' anti-inflammatory effects in hypercholesterolemia involve mitigating oxysterol-induced monocyte activation.
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