Mechanisms underlying stress-induced changes in the cytokine network : implications for cancer progression

Abstract

Numerous studies have reported that exposure to psychological stress suppresses various aspects of the innate and adaptive immune responses, including impairment of the cytokine network. In agreement with these reports, in this thesis it was observed that exposure to acute and chronic restraint stress altered cytokine production following an in vivo LPS challenge in mice. The innate IFN-γ response was impaired, with reduced IFN-γ production, signaling, expression of IFN-γ inducible genes and the expression of IFN-γ inducing proteins IL-12 and IL-15. In addition, the anti-inflammatory cytokines IL-10 and the IL-10 family member, IL-19, were augmented following exposure to acute and chronic stress. It has been suggested that the stress-induced increase in IL-10 may mediate the stress-induced suppression of the innate IFN-γ response, due to its ability to inhibit the production of pro-inflammatory cytokines. However, the findings from this thesis indicate that stress-induced inhibition of the innate IFN-γ response occurs independent of IL-10 production. To further understand the mechanisms behind stress-induced alteration of the cytokine network, the contribution of the stress hormones were investigated. Glucocorticoids and catecholamines are released following stress-induced activation of the HPA and SAM axis and they can directly alter immune function via specific receptors found on immune cells. The findings from this thesis suggest that glucocorticoids and catecholamines play distinct, but parallel roles in the stress-induced alteration of the cytokine network. Glucocorticoids, acting via GR, contribute to stress-induced suppression of the innate IFN-γ response, however, catecholamines, acting via pi-AR, mediate stress-induced augmentation of IL-10 and IL-19.