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Published on: August 1, 2012
Reblastatins Inhibit Phenotypic Changes of Monocytes/Macrophages in a Milieu Rich in 27-Hydroxycholesterol
Jeongyoon Choi1, Bo-Young Kim1, Yonghae Son1
1Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea.
Abstract:
We investigated effects of reblastatins on phenotypic changes in monocytes/macrophages induced by 27-hydroxycholesterol (27OHChol). Treatment of THP-1 monocytic cells with reblastatin derivatives, such as 17-demethoxy-reblastatin (17-DR), 18-dehydroxyl-17-demethoxyreblastatin (WK88-1), 18-hydroxyl-17-demethoxyreblastatin (WK88-2), and 18-hydroxyl-17-demethoxy-4,5-dehydroreblastatin (WK88-3), resulted in blockage of CCL2, CCL3, and CCL4 expression at the transcription and protein levels, which, in turn, impaired migration of monocytes/macrophages and Jurkat T cells expressing CCR5, and almost complete inhibition of transcription of M1 marker cytokines, like CXCL10, CXCL11, and TNF-α. Reblastatins also downregulated surface CD14 as well as soluble CD14 along with inhibition of LPS response and matrix metalloprotease-9 expression. Surface levels of mature dendritic cell (mDC)-specific markers, including CD80, CD83, CD88, CD197, and MHC class I and II molecules, were remarkably down-regulated, and 27OHChol-induced decrease of endocytic activity was recovered following treatment with 17-DR, WK88-1, WK88-2, and WK88-3. However, 15-hydroxyl-17-demethoxyreblastatin (DHQ3) did not affect the molecular or functional changes in monocytic cells induced by 27OHChol. Furthermore, surface levels of CD105, CD137, and CD166 were also down-regulated by 17-DR, WK88-1, WK88-2, and WK88-3, but not by DHQ3. Collectively, results of the current study indicate that, except DHQ3, reblastatins regulate the conversion and differentiation of monocytic cells to an immunostimulatory phenotype and mDCs, respectively, which suggests possible applications of reblastatins for immunomodulation in a milieu rich in oxygenated cholesterol molecules.
Insights
Reblastatins, except DHQ3, modulate monocyte/macrophage differentiation and function, inhibiting inflammatory markers and restoring endocytic activity. These compounds show potential for immunomodulation in conditions involving oxygenated cholesterol.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- 27-hydroxycholesterol (27OHChol) induces phenotypic changes in monocytes/macrophages.
- Oxygenated sterols can influence immune cell function and differentiation.
- Understanding modulators of these cellular responses is crucial for immune system regulation.
Purpose of the Study:
- To investigate the effects of reblastatins on monocytes/macrophages altered by 27OHChol.
- To determine the impact of specific reblastatin derivatives on immune cell markers and functions.
- To explore the potential of reblastatins as immunomodulatory agents.
Main Methods:
- Treatment of THP-1 monocytic cells with various reblastatin derivatives (e.g., 17-DR, WK88-1, WK88-2, WK88-3, DHQ3).
- Analysis of gene and protein expression for chemokines (CCL2, CCL3, CCL4), M1 markers (CXCL10, CXCL11, TNF-α), and cell surface markers (CD14, CD80, CD83, CD88, CD197, MHC I/II, CD105, CD137, CD166).
- Assessment of monocyte/macrophage migration, LPS response, matrix metalloprotease-9 expression, and endocytic activity.
Main Results:
- Reblastatins (except DHQ3) blocked CCL2, CCL3, CCL4 expression, impairing monocyte/macrophage and T cell migration.
- Reblastatins inhibited M1 marker cytokines and downregulated CD14, LPS response, and MMP-9.
- Reblastatins reversed 27OHChol-induced decrease in endocytic activity and modulated mature dendritic cell (mDC) markers.
Conclusions:
- Reblastatins, excluding DHQ3, effectively regulate monocytic cell differentiation towards an immunostimulatory phenotype and mDCs.
- These findings suggest reblastatins' potential therapeutic application in modulating immune responses in hypercholesterolemic environments.
- Reblastatins demonstrate significant immunomodulatory capabilities by altering key cellular pathways involved in inflammation and differentiation.
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