Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Psychosocial distress, characterized by increased perceived stress, anxiety and mood disturbance, is a common response of women to a diagnosis of breast cancer (Northouse, 1992; Pettingale et al., 1988; Stark and House, 2000; Witek-Janusek et al., 2007). This psychosocial distress leads to activation of the hypothalamic-pituitary-adrenocortical (HPA) axis and increased circulating glucocorticoids (GCs) (Chrousos, 2000; Chrousos and Gold, 1992; Schoneveld and Cidlowski, 2007). Increased psychosocial distress and increased HPA activation can lead to immune dysregulation consisting of reduced natural killer (NK) cell activity (NKCA) (Biondi, 2001; Kiecolt-Glaser et al., 1987; Kiecolt-Glaser et al., 2002; Witek-Janusek et al., 2008; Witek-Janusek et al., 2007). This is of particular relevance to women with breast cancer as altered immune cell function is important for tumor control (Curcio et al., 2003; D'Anello et al., 2010; Diefenbach and Raulet, 2002; Hartman et al., 2011; Kishimoto, 2005; Knupfer and Preiss, 2007; Street et al., 2001; van den Broek et al., 1996). The psychological distress in response to a diagnosis of breast cancer diagnosis has relevance for women with breast cancer, as it may contribute to poor cancer outcome.

Yet little is known about the molecular mechanism(s) by which psychosocial distress results in NK cell dysregulation. The overall purpose of this project was to evaluate a potential mechanism posited to underlie altered NK cell function observed in women with breast cancer. Increased psychosocial distress increases GCs like cortisol which can impact NK cell function; therefore cortisol levels were measured. Morning cortisol rise inversely correlated with NKCA, such that women with decreased NKCA exhibited an elevation in the morning cortisol rise. Additionally, in vitro treatment of a human NK cell line, NK92 cells, treated with a synthetic GC (dexamethasone) resulted in decreased NKCA. Together these results suggest that cortisol altered lytic function of NK cells. As GCs have been shown to alter cell function by altering epigenetic patterns, global histone modifications were investigated. In both ex vivo analysis of NK cells derived from peripheral blood of women with breast cancer and NK92 cells treated with GCs significant reductions in global acetylation of histone 4 lysine 8 (H4-K8-Ac) were observed, when compared to the age-matched Control women or untreated NK92 cells, respectively. These reductions in H4-K8-Ac correlated with NK cell lytic function as measured by NKCA and intracellular perforin levels in NK cells. Further others show GCs alter epigenetic patterns through recruitment of HDACs, thus this was investigated. Findings show decreased global H4-K8-Ac patterns in NK cells were associated with increased nuclear localization of HDAC2, suggesting that GCs recruit HDAC2 into the nucleus causing decreased global H4-K8-Ac and NKCA. These data identify decreased global H4-K8-Ac and increased nuclear localization of HDAC2 as potential markers of decreased NK cell lytic activity in women experiencing psychosocial distress. This mechanistic insight advances the field of psychoneuroimmunology by identifying both an epigenetic modification (H4-K8-Ac) and a chromatin remodeling protein (HDAC2) as indicators of GC mediated immune dysregulation in NK cells of women experiencing psychosocial distress.

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