Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Psychological stress can impact immune function through altered glucocorticoid production. Natural killer (NK) cells and their effector functions are particularly susceptible to both psychological stress as well as exogenous glucocorticoids. The purpose of this study was to assess the impact of chronic glucocorticoid (GC) exposure on NK cells to investigate the immune dysregulation associated with periods of psychological stress.

Chronic in vitro treatment of the NK92 cell line produced a dichotomous NK phenotype with enhanced proinflammatory cytokine production yet reduced NK cell lytic activity (NKCA). This dichotomy was at the individual cell level where mRNA and protein levels for proinflammatory cytokines increased while mRNA and protein levels for lytic molecules decreased. For the lytic molecules, reduced transcription related to recruitment of histone deacetylase 2 (HDAC2) with concomitant reduction in H3K9-acetylation (Ac). In contrast, IL-6 and IFN-g were primed for increased transcription upon cellular activation demonstrating increased H4K8Ac, increased accessibility of the chromatin structure, and concomitant loss of HDAC1 and HDAC3 at regulatory loci. These results demonstrate chronic GC exposure to impact NK effector function through the modification of the epigenetic status of NK effector genes through HDAC redistribution and subsequent epigenetic changes in a promoter specific manner.

These observations were used to investigate the alterations in immune function during periods of psychological distress, at or within 10 days of cancer diagnosis. The diagnosis of breast cancer is attributed with increased stress, depressive mood, anxiety, mood and sleep disturbance. The perceived stress of cancer diagnosis was associated with increased daily cortisol production. A similar dichotomous immune phenotype characterized by decreased NKCA and enhanced proinflammatory cytokine production was observed in the peripheral blood mononuclear cells (PBMC) of stressed individuals and was related to the increased activation of the HPA axis. Epigenetic analysis of PBMC demonstrated enhanced production of proinflammatory cytokines related to H3K9-acetylation within critical regulatory regions. Statistical analysis demonstrated that increased proinflammatory cytokine production by stress is partially mediated by promoter specific acetylation patterns on H3K9. In conjunction with pathways elucidated in vitro we conclude that epigenetic mechanisms regulate immune function during periods of psychological stress.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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