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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-? 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.

SUBMITTER: Kim BY

PROVIDER: S-EPMC7041177 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Prednisolone suppresses the immunostimulatory effects of 27-hydroxycholesterol.

Kim Bo-Young BY Son Yonghae Y Kim Min Su MS Kim Koanhoi K

Experimental and therapeutic medicine 20200116 3

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 e ...[more]

PMID: 32194655

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Project description:Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1nih ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17β-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Prednisolone suppresses the immunostimulatory effects of 27-hydroxycholesterol.

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Prednisolone suppresses the immunostimulatory effects of 27-hydroxycholesterol.

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