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Histone deacetylase inhibition results in decreased macrophage CD9 expression
Xue-Qing Wang1, M Leticia Alfaro, Glenn F Evans
1Division of Cardiovascular Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Insights
Histone deacetylase (HDAC) inhibitors, like trichostatin A (TSA), reduce CD9 expression in macrophages. This modulation of membrane proteins may impact macrophage function and interactions.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Histone deacetylase (HDAC) inhibitors are known to influence myeloid cell differentiation.
- Tetraspanin CD9 is a cell surface antigen expressed on various immune cells.
Purpose of the Study:
- To investigate the effects of the HDAC inhibitor trichostatin A (TSA) on CD9 expression in primary murine macrophages.
- To compare the effects of TSA with interferon-gamma (IFN-gamma) on macrophage gene expression.
Main Methods:
- Primary murine macrophages were treated with TSA.
- CD9 protein and message expression were analyzed.
- Expression of other surface markers (CD54, CD11b) was assessed.
- Histone H4 acetylation levels were measured.
- Transcriptional profiling was performed.
Main Results:
- TSA significantly inhibited CD9 protein and message expression in a concentration-dependent manner, with optimal effects at 48 hours.
- TSA treatment led to increased histone H4 acetylation.
- While both TSA and IFN-gamma reduced CD9 expression, they had distinct effects on other genes, such as CD14.
- TSA had minimal effects on CD54 and CD11b expression.
Conclusions:
- HDAC inhibition by TSA modulates macrophage function through alterations in cell surface protein expression, specifically CD9.
- Changes in membrane proteins involved in matrix interactions may be a key mechanism by which HDAC inhibitors affect macrophage behavior.
- HDAC inhibitors offer a distinct regulatory pathway for macrophage function compared to cytokines like IFN-gamma.
Abstract:
Histone deacetylase (HDAC) inhibitors have been demonstrated to regulate myeloid cell differentiation. In the present study the effects of the HDAC inhibitor trichostatin A (TSA) on the tetraspanin cell surface antigen CD9 were determined in primary murine macrophages. TSA inhibited CD9 protein and message expression and was optimal by 48 h. TSA did not induce similar effects on other surface markers and resulted in a modest increase or no effect on CD54 and CD11b, respectively. These effects were concentration dependent and concomitant with increased histone H4 acetylation. While interferon-gamma (IFN-gamma) and TSA had similar effects on CD9 expression, transcriptional profiling demonstrated significant differences in the genes activated by these stimuli. Notably CD14 message was down-regulated by IFN-gamma while increased by TSA. These results demonstrate that HDAC inhibition may modulate macrophage function in part through changes in the expression of membrane proteins associated with matrix interactions.