Elsevier

Pharmacological Reports

Volume 65, Issue 6, November–December 2013, Pages 1655-1662
Pharmacological Reports

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

https://doi.org/10.1016/S1734-1140(13)71527-5Get rights and content

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.

Section snippets

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction and depression

Dysregulation of the neuroimmune-endocrine system is accepted as one of the fundamental biological mechanisms that underlie psychiatric disorders [17, 28, 32]. Earlier investigations on the pathophysiology of depression have provided strong evidence that depressed patients manifest HPA axis hyperactivity [1]. Differential adrenocortical activity between depressed patients and normal subjects is regarded as the most reproducible finding in all of biological psychiatry. An additional established

Cytokine-induced stimulation of the HPA axis under basal and stress conditions

Cytokines, generally secreted by cells of the immune system, may also be synthesized and secreted by non-immune cells in order to signal neuroimmune cells. Interleukin-1β is one of the major proinflammatory cytokines involved in the regulation of HPA axis activity in the brain [15]. IL-1β is expressed in all components of the HPA axis, affects the secretion of CRH from the hypothalamus, ACTH from the pituitary and glucocorticoids from the adrenal cortex. Furthermore, IL-1β may also directly

Brain NO/NOS systems in IL-1β- and stress-induced stimulation of the HPA axis

Nitric oxide (NO) is a signaling molecule for various cell types and systems, and also serves as a neurotransmitter in the brain. Under physiological conditions, neuronal NO synthase (nNOS) is constitutively expressed, and it constitutes the major isoenzyme of NOS in the brain. Inducible NO synthase (iNOS) is undetectable under basal conditions, and it is upregulated in response to various stimuli such as inflammatory cytokines and stress [27]. NO generated by iNOS in the brain is involved in

Involvement of brain PG/COX systems in IL-1β- and stress-activation of the HPA axis

Prostaglandins are products of the cyclooxygenase (COX) pathway of arachidonic acid metabolism. COX-1 is constitutively expressed in a variety of cells and tissues. The other isoform, COX-2, is the product of an immediate early response gene in inflammatory cells. The expression of COX-2 is induced by endotoxins or cytokines including IL-1 and TNF-α. In the brain, COX-2 may be expressed constitutively and is regarded as the predominant isoform; its basal expression appears to be regulated by

Concluding remarks

Dysregulation of the neuroimmune-endocrine system is accepted as one of the fundamental biological mechanisms that underlie psychiatric disorders.

Hyperactivity of the HPA axis is one of the most reliable biological findings in patients suffering from major depression. This hyperactivity is caused by diminished feedback inhibition of GC-induced reduction of HPA axis signaling in healthy individuals, as well as increased CRH secretion from the hypothalamic PVN and extrahypothalamic neurons.

Acknowledgment

This research was supported by grant: POIG 01.01.02-12-004/09-00, financed by the European Regional Development Fund.

References (34)

  • S. Hayley et al.

    The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity

    Neuroscience

    (2005)
  • C. Marquez et al.

    The hypothalamicpituitary- adrenal and glucose responses to daily repeated immobilization stress in rats: individual differences

    Neuroscience

    (2004)
  • K. Mizoguchi et al.

    Chronic stress attenuates glucocorticoid negative feedback involvement of the prefrontal cortex and hippocampus

    Neuroscience

    (2003)
  • R.J. Nelson et al.

    Pleiotropic contributions of nitric oxide to aggressive behavior

    Neurosci Biobehav Rev

    (2006)
  • C.M. Pariante et al.

    The HPA axis in major depression: classical theoriesand new developments

    Trends Neurosci

    (2008)
  • E. Senba et al.

    Stress-induced expression of immediate early genes in the brain and peripheral organs of the rats

    Neurosci Res

    (1997)
  • N. Yamaguchi et al.

    Nitric oxide synthase isozymes in spinally projecting PVN neurons are involved in CRF-induced sympathetic activation

    Auton Neurosci

    (2009)

    • Cited by (0)

    View full text
    Copyright © 2013 Institute of Pharmacology Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.