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Glucocorticoid dysregulation of natural killer cell function through epigenetic modification
Karen Krukowski1, Justin Eddy, Kelly Loster Kosik
1Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA.
Brain, Behavior, and Immunity
|July 27, 2010
Summary
Psychological distress impairs natural killer cell activity (NKCA) via glucocorticoids. This study reveals epigenetic mechanisms, specifically reduced histone acetylation, underlie this suppression, impacting immune response.
Area of Science:
- Immunology
- Epigenetics
- Cell Biology
Background:
- Psychological distress is known to reduce natural killer cell activity (NKCA) and cytokine balance.
- Stress-induced glucocorticoids are implicated in suppressing NKCA and altering cytokine production.
- The precise mechanisms by which glucocorticoids affect NK cells require further elucidation.
Purpose of the Study:
- To investigate the epigenetic mechanisms underlying glucocorticoid-mediated effects on NK cells.
- To evaluate the impact of dexamethasone on NK92 cell function and epigenetic modifications.
- To determine if histone deacetylase inhibition can reverse glucocorticoid-induced suppression of NK cell function.
Main Methods:
- Treatment of human NK92 cells with dexamethasone (10⁻⁷M).
- Assay of NKCA, tumor cell binding, granule constituent production, cytokine production (IL-6, TNF alpha, IFN gamma), and LFA-1 expression.
- Analysis of global histone acetylation, specific histone modifications, and promoter accessibility of effector genes.
- Treatment with a histone deacetylase inhibitor to assess functional recovery.
Main Results:
- Dexamethasone significantly reduced NKCA by impairing tumor cell binding and decreasing perforin and granzyme B production.
- Glucocorticoids reduced IL-6, TNF alpha, and IFN gamma production and lowered LFA-1 surface expression.
- Dexamethasone decreased global histone acetylation and promoter accessibility for key effector genes, an effect reversed by histone deacetylase inhibition.
- Histone deacetylase inhibitor treatment restored NKCA and IFN gamma production.
Conclusions:
- Glucocorticoids dysregulate NK cell function, at least partly, through epigenetic mechanisms involving reduced histone acetylation.
- Epigenetic modifications decrease promoter accessibility, leading to reduced expression of essential effector proteins in NK cells.
- These findings highlight a novel epigenetic pathway through which stress can impair immune surveillance by NK cells.
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