Prednisolone suppresses the immunostimulatory effects of 27‑hydroxycholesterol

Abstract

In cholesterol-fed rabbits, site-specific targeting of prednisolone nanoparticles results in significantly reduced neo-intimal inflammation with a decreased infiltration of monocytes/macrophages. To understand the molecular mechanisms underlying this, the current study investigated whether prednisolone affects the immune attributes of 27-hydroxycholesterol (27OHChol), the major oxidized cholesterol molecule in circulation and tissue, in human (THP-1) monocyte/macrophage cells. THP-1 cells were exposed to 27OHChol in the presence of prednisolone followed by evaluation of inflammatory molecules at mRNA and protein levels by quantitative PCR, western blotting, ELISA and flow cytometry. The results revealed that prednisolone suppressed the 27OHChol-mediated expression of various macrophage (M)1 markers, including chemokine ligand 2, C-X-C chemokine motif 10, tumor necrosis factor-α and CD80. Treatment also impaired the 27OHCHol-enhanced migration of monocytic cells, downregulated the 27OHChol-induced cell surface expression of CD14 and inhibited the release of soluble CD14 comparable with a weakened lipopolysaccharide response. Furthermore, prednisolone suppressed the 27OHChol-induced expression of matrix metalloproteinase 9 at the transcriptional and protein level, as well as the phosphorylation of the p65 subunit. Prednisolone increased the transcription of CD163 and CD206 genes, and augmented the 27OHChol-induced transcription of CD163 without upregulating the 27OHChol-induced surface protein level of the gene. The results indicated that prednisolone inhibited the polarization of monocytes/macrophages towards the M1 phenotype, which that the immunostimulatory effects of 27OHCHol were being regulated and the immune responses in conditions that were rich in oxygenated cholesterol molecules were being modulated.

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

“…It has also been reported that it damages ZO-1, a protein in the tight junction of blood vessels, causing blood leakage from blood vessels, tissue leakage from tissues, and vision loss due to leakage of ocular fluid ( 46 ). Together with previous findings, our results suggest that glucocorticoids may be beneficial in the treatment of inflammatory and autoimmune diseases that occur in the setting of hypercholesterolemia, such as atherosclerosis, due to their potent anti-inflammatory and immunosuppressive effects ( 47 48 49 ). Taken together, these results show that glucocorticoids, a widely used clinical drug, effectively suppress the inflammatory immune response triggered by increased oxysterols in the body.…”

Role of reactive oxygen species in regulating 27-hydroxycholesterol-induced apoptosis of hematopoietic progenitor cells and myeloid cell lines

“…Our results revealed that normal HSPC indeed exhibits an increased expression of ERα in response to 27HC treatment. We have previously explored the molecular pathways affected by 27HC treatment in THP1 cells [ 47 ]. To assess whether 27HC affects HSPC, we exposed HSPCs in BM cells to 6.2 µM 27HC for 24 h (Fig.…”

Miconazole Suppresses 27-Hydroxycholesterol-induced Inflammation by Regulating Activation of Monocytic Cells to a Proinflammatory Phenotype

“…Therefore, drugs that regulate the activities of 27OHChol are likely to have antiinflammatory or immunosuppressive effects. Accordingly, immunosuppressive drugs, such as dexamethasone, prednisolone, and cyclosporine A, have been reported to inhibit the 27OHChol-induced activation of monocytes (Kim et al, 2017;Lee et al, 2019;Kim et al, 2020). In addition, diclofenac, a non-steroidal anti-inflammatory drug, and reblastatin, which exhibits anticancer effects, and 4-Omethylalpinumisoflavone, which displays anti-inflammatory effects against LPS, suppress 27OHChol-induced monocytic cell activation (Son et al, 2017;Lee et al, 2019;Choi et al, 2020).…”