Review Cytokines,prostaglandins and nitric oxide in the regulation of stress-response systems

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is accepted as one of the fundamental biological mechanisms that underlie major depression. This hyperactivity is caused by diminished feedback inhibition of glucocorticoid (GC)-induced reduction of HPA axis signaling and increased corticotrophin-releasing hormone (CRH) secretion from the hypothalamic paraventricular nu-cleus (PVN) and extra-hypothalamic neurons. During chronic stress-induced inhibition of systemic feedback, cytosolic glucocorti-coid receptor (GR) levels were significantly changed in the prefrontal cortex (PFC) and hippocampus, both structures known to be deeply involved in the pathogenesis of depression. Cytokines secreted by both immune and non-immune cells can markedly affect neurotransmission within regulatory brain circuits related to the expression of emotions; cytokines may also induce hormonal changes similar to those observed following exposure to stress. Proinflammatory cytokines, including interleukin-1b (IL-1b), interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) are implicated in the etiologies of clinical depression and anxiety disorders. Prolonged stress responses and cytokines impair neuronal plasticity and stimulation of neurotransmission. Exposure to acute stress and IL-1b markedly increased IL-1b levels in the PFC, hip-pocampus and hypothalamus, as well as overall HPA axis activity. Repeated stress sensitized the HPA axis response to IL-1b. Inflammatory responses in the brain contribute to cellular damage associated with neuropsychiatric diseases related to stress. Physical, psychological or combined-stress conditions evoke a proinflammatory response in the brain and other systems, characterized by a com-plex release of several inflammatory mediators including cytokines, prostanoids, nitric oxide (NO) and transcription factors