title: Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems.
abstract: 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 nucleus (PVN) and extra-hypothalamic neurons. During chronic stress-induced inhibition of systemic feedback, cytosolic glucocorticoid 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-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) 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-1β markedly increased IL-1β levels in the PFC, hippocampus and hypothalamus, as well as overall HPA axis activity. Repeated stress sensitized the HPA axis response to IL-1β. 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 complex release of several inflammatory mediators including cytokines, prostanoids, nitric oxide (NO) and transcription factors. Induced CRH release involves IL-1, IL-6 and TNF-α, for stimulation adrenocorticotropic hormone (ACTH) release from the anterior pituitary. NO also participates in signal transduction pathways that result in the release of corticosterone from the adrenal gland. NO participates in multiple interactions between neuroendocrine and neuroimmune systems in physiological and pathological processes. Neuronal NO synthase (nNOS) modulates learning and memory and is involved in development of neuropsychiatric diseases, including depression. Nitric oxide generated in response to stress exposure is associated with depression-like and anxiety-like behaviors. In the central nervous system (CNS), prostaglandins (PG) generated by the cyclooxygenase (COX) enzyme are involved in the regulation of HPA axis activity. Prior exposure to chronic stress alters constitutive (COX-1) and inducible (COX-2) cyclooxygenase responses to homotypic stress differently in the PFC, hippocampus and hypothalamus. Both PG and NO generated within the PVN participate in this modulation. Acute stress affects the functionality of COX/PG and NOS/NO systems in brain structures. The complex responses of central and peripheral pathways to acute and chronic stress involve cytokines, NO and PG systems that regulate and turn off responses that would be potentially harmful for cellular homeostasis and overall health.
authors.affiliation: Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. gadek@if-pan.krakow.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Gądek-Michalska
authors.forename: Joanna
authors.initials: J
authors.lastname: Tadeusz
authors.forename: Paulina
authors.initials: P
authors.lastname: Rachwalska
authors.forename: Jan
authors.initials: J
authors.lastname: Bugajski
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D016207:Cytokines; D011453:Prostaglandins; D009569:Nitric Oxide