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. Author manuscript; available in PMC: 2015 May 11.
Published in final edited form as: Brain Behav Immun. 2012 Dec 20;31:105–114. doi: 10.1016/j.bbi.2012.12.008

Fig. 3.

Fig. 3

Pro inflammatory cytokines activate the HPA axis. Hypothalamic CRH stimulates the pituitary, which in turn releases ACTH, leading to stimulation of the adrenal cortex. Released glucocorticoid provides negative feedback on the HPA axis via the hypothalamus and pituitary, as well as hippocampus. Glucocorticoids also suppress pro-inflammatory cytokines under normal conditions, although paradoxically cytokine levels remain high in depressed patients. Cytokine-activation of the HPA axis in the presence of elevated glucocorticoid levels could result from disruption of HPA axis homeostatic mechanisms: that is, inflammatory cytokines activate each step of the HPA axis, including the hypothalamus, pituitary and adrenal cortex. This occurs at the same time that cytokines disrupt glucocorticoid receptor-mediated negative feedback (see text). In this model, inflammatory cytokines in the brain are directly activated by stress. Also, brain pro-inflammatory cytokines can reciprocally affect peripheral cytokines, which can activate the HPA axis and also influence other brain regions via several possible mechanisms (see text). Increased pro-inflammatory cytokines in both brain and periphery disturb negative feedback by glucocorticoids. Abbreviations: ACTH, adrenocorticotropic hormone; CORT, corticosterone; CRH, corticotropin-releasing hormone.