The stress response and the hypothalamic‐pituitary‐adrenal axis: from molecule to melancholia Next Section Abstract Organisms survive by maintaining equilibrium with their environment. The stress system is critical to this homeostasis. Glucocorticoids modulate the stress response at a molecular level by altering gene expression, transcription, and translation, among other pathways. The effect is the inhibition of the functions of inflammatory cells, predominantly mediated through inhibition of cytokines, such as IL‐1, IL‐6, and TNF‐α. The central effectors of the stress response are the corticotrophin‐releasing hormone (CRH) and locus coeruleus‐norepinephrine (LC‐NE)/sympathetic systems. The CRH system activates the stress response and is subject to modulation by cytokines, hormones, and neurotransmitters. Glucocorticoids also modulate the growth, reproductive and thyroid axes. Abnormalities of stress system activation have been shown in inflammatory diseases such as rheumatoid arthritis, as well as behavioural syndromes such as melancholic depression. These disorders are comparable to those seen in rats whose CRH system is genetically abnormal. Thus, the stress response is central to resistance to inflammatory and behavioural syndromes. In this review, we describe the response to stress at molecular, cellular, neuroendocrine and behavioural levels, and discuss the disease processes that result from a dysregulation of this response, as well as recent developments in their treatment. Previous Section Next Section Introduction Organisms survive by maintaining a dynamic equilibrium with their environment. The organization of this homeostasis exists at molecular, cellular, physiological and behavioural levels. Stress is a state of threat to this equilibrium, and adaptation to stress, or allostasis, confers a survival advantage. Successful adaptation requires not only the ability to respond to stress, but also the ability to control the stress response appropriately. This stress system is tonically active, but both physical and emotional stressors that exceed a critical threshold increase its activity further. The hypothalamic‐pituitary‐adrenal (HPA) axis and the sympathetic and adrenomedullary (sympathetic) systems are the peripheral limbs of the stress system. Increased system activation as a result of stress leads to central and peripheral changes, which facilitate behavioural adaptation and redirection of energy to the central nervous system, muscle, and stressed body sites. These changes serve to promote homeostasis. HPA axis activation results in glucocorticoid secretion. The principal role of glucocorticoids during the stress response is thought to be restraint of the effectors of the stress response. We review the response to stress from a molecular to a behavioural level and discuss the disease processes that may result from a dysregulation of this response. Previous Section Next Section The molecular response to stress Glucocorticoids are the effectors of the HPA limb of the stress system. Stress and non‐stress activities of glucocorticoids are regulated through two different types of glucocorticoid receptors. The type 1, high‐affinity or mineralocorticoid receptor (MR) mediates non‐stress circadian fluctuations in glucocorticoids and is primarily activational. The type 2, low‐affinity or glucocorticoid receptor (GR), mediates stress levels of glucocorticoids, and is inhibitory in some systems and activational in others.1 Glucocorticoid affinity for the MR is 10 times that of the GR.2 Glucocorticoid receptors have a widespread distribution throughout tissues. The glucocorticoid cytoplasmic receptor protein belongs to the phylogenetically conserved superfamily of nuclear hormone receptors.3 The receptor contains three major functional domains. The carboxyterminal binds glucorticoid. This binding leads to the dissociation of heat‐shock protein, which induces a conformational change in the glucocorticoid receptor molecule. This, in turn, leads to nuclear translocation of the glucocorticoid receptor. In the nucleus, the midregion binds to specific sequences of DNA known as glucocorticoid‐responsive elements (GREs). This binding facilitates the activation of target genes by the aminoterminal sequence4 (Figure1). Glucocorticoids may modulate immune responses in numerous ways, including through gene expression, transcription, translation, post‐translational processing, protein secretion, and cell progenitor proliferation and differentiation. Cytokine inhibition accounts for many of the inhibitory effects on the immune response during stress. Glucocorticoids inhibit cytokine production by altering mRNA stability at the level of gene expression. Their actions may be mediated directly (Type 1 mechanism) or indirectly (Type 2 mechanism).5 For example, glucocorticoids directly decrease transcription of the genes for interleukin‐6 (IL‐6) and interleukin‐1β, thus decreasing their production by immune cells. In contrast, the immune response is indirectly suppressed by glucocorticoids through inhibition of pro‐inflammatory transcription factors such as nuclear factor‐κB (NF‐κB) and activating protein‐1 (AP‐1).6 NF‐κB is a heterodimer, which is found in the cytoplasm bound to IκBα and IκBβ. These proteins prevent NF‐κB from entering the nucleus.7 NF‐κB is activated by many stressors (viral infection, oxidants, cytokines, and antigens).8 Activation leads to the release of IκB, allowing passage of NF‐κB into the nucleus, where it binds to specific sequences in the promoter regions of target genes. NF‐κB increases the expression of the genes for many cytokines, enzymes, and adhesion molecules in inflammatory diseases.9 In turn, pro‐inflammatory cytokines such as IL‐1β and tumour necrosis factor‐α (TNF‐α) activate NF‐κB, thus perpetuating local inflammatory responses (Figure1).9 Glucocorticoids are potent inhibitors of the activation of NF‐κB, which may account for many of their anti‐inflammatory actions. Generalized glucocorticoid resistance can result from quantitative or qualitative defects in the GR of a system.10 More recently, a polymorphism in the glucocorticoid receptor gene has been described which may result in increased glucocorticoid sensitivity.11 There are also numerous molecular determinants of glucocorticoid for killing human sensitivity.
Posted on: Sat, 22 Jun 2013 23:17:50 +0000