Successful antidepressant therapy restores the disturbed interplay between TNF-alpha system and HPA axis

Himmerich, Hubertus; Binder, E. B.; Künzel, Heike; Schuld, Andreas; Lucae, Susanne; Uhr, Manfred; Pollmächer, Thomas; Holsboer, Florian; Ising, Marcus

doi:10.1055/s-2005-918716

Cited by 32 publications

(45 citation statements)

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“…A role for TNF-a in anxiety-like behavior is supported by studies demonstrating that chronic peripheral administration of TNF-a antagonists reduce levels of depression and anxiety in conditions, including chronic pain and RA (Uguz et al, 2009) while genetic knockout of TNF-a lowers anxiety-like behavior in young mice (Camara et al, 2013). The role of TNF-a in regulating emotional responses within the CNS is yet to be determined with suggestions that TNF-a may be involved in the regulation of the serotonin transporter pathway, as well as stimulation of the hypothalamic-pituitary axis, which are involved in generating emotional responses (Bayramgurler et al, 2013;Himmerich et al, 2006;Zhu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

Camara

Corrigan

Jaehne

et al. 2014

Neuropsychopharmacol

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Section: Discussionmentioning

confidence: 99%

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

Camara

Corrigan

Jaehne

et al. 2014

Neuropsychopharmacol

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“…For example, an increase of IL-6 concentration is significantly correlated with disturbance of the HPA axis, which is generally displayed as elevated cortisol in depressive patients [24] . TNF-α and its soluble receptors released during infection and inflammation activate the HPA system, resulting in the release of cortisol [58] . Over-activation of the HPA axis contributes to both glucocorticoid receptor feedback insensitivity and the over-production of other corticotropin secretagogs insensitive to glucocorticoid feedback in depression [59] .…”

Section: Hpa Axis Activationmentioning

confidence: 99%

“…TNF-α and its soluble receptors released during infection and inflammation activate the HPA system, resulting in the release of cortisol [58] . Over-activation of the HPA axis contributes to both glucocorticoid receptor feedback insensitivity and the over-production of other corticotropin secretagogs insensitive to glucocorticoid feedback in depression [59] .…”

Section: Hpa Axis Activationmentioning

confidence: 99%

Inflammation: a mechanism of depression?

Han

2014

Neurosci. Bull.

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In recent decades, major depression has become more prevalent and research has shown that immune activation and cytokine production may be involved. This review is mainly focused on the contribution of infl ammation to depression. We fi rst briefl y introduce the infl ammatory biomarkers of depression, then discuss the sources of cytokines in the brain, and fi nally describe the neuroimmunological mechanisms underlying the association between infl ammation and depression.Keywords: depression; infl ammation; cytokines; hypothalamic-pituitary-adrenal axis; 5-HT; neuroplasticity ·Review· IntroductionThe prevalence of major depression has increased dramatically over the past few decades [1] , and women are nearly twice as likely as men to develop depressive disorder [2] . Depression is classified as a brain disorder, but its symptomatology includes some behaviors that also occur during chronic infl ammatory stress [3] . Research has shown that immune activation and the production of cytokines may be involved in depression [4] , so this relationship has received much attention. In fact, three causal pathways have been proposed: depression to inflammation, inflammation to depression, and a bidirectional relationship [5] . In this review, we focus on the impact of inflammation on depression and the underlying mechanisms. Cytokines are small cell-signaling proteins that mediate and regulate immune responses and inflammation, and can be divided into two categories:the pro-inflammatory cytokines interleukin (IL)-1 β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, and the anti-inflammatory cytokines IL-1Rα, IL-4, IL-10, and transforming growth factor (TGF)-β1. Generally, t he proinfl ammatory cytokines promote systemic infl ammation and are essential for the initiation of an infl ammatory response to disease [6] , while the anti-inflammatory cytokines antagonize these actions to reduce inflammation and promote healing [6,7] . Moreover, some cytokines play dual roles [8] . In the central nervous system (CNS), the cellular source, function, and mechanisms of action of cytokines differ from those in the periphery. In the following, we briefl y introduce the current research on infl ammatory biomarkers of depression. Infl ammatory Biomarkers of DepressionSo far, there are neither universally accepted or defi nitive biomarkers of depression [9] , nor effective methods to assess the severity, endophenotypes, or response to treatment [10] .However, sufficient evidence has suggested changes in the circulating levels of cytokines in depressed patients, which can be reversed by antidepressant treatments [11,12] .So, many studies have aimed to clarify the neurobiological changes in depression and to establish inflammatory biomarkers. The peripheral levels of IL-6, TNF-α, and IL-1β are increased in patients with depression [13][14][15][16][17] , and antidepressant treatments reverse this effect [18][19][20] . These consistent results demonstrate that IL-6, TNF-α, and IL-1β are putative biomarkers for depression. However, due to the he...

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“…30 Also TNFa, a circulating state marker for depression may stimulate CRF production. 31,74 In addition, TNFa is produced by astrocytes and ependymal cells. 32 In the present study, we did not find a change of TNFa or IL1b in mRNA levels in the PVN in depressed patients.…”

Section: Cytokinesmentioning

confidence: 99%

“…MR and GR can form hetero-and homodimers that differ in their activity of gene regulation. A change in the balance of MR/GR ratio in depressed patients may contribute to the change in transcription rate of CRF [16][17][18][19][20] ; (2) the CRF receptors, that is, CRFR1 that stimulates CRF production 21,22 and CRFR2 that opposes this action 23 ; (3) alterations in vasopressinergic systems that potentiate effects of CRF 24 and the AVP receptor 1a (AVPR1A) that is involved in anxiety/ depressionrelated behavior 25 ; oxytocin (OXT) that attenuates the stress response was found to be increased in the PVN only in melancholic depression 26 ; (4) cAMP-response element-binding protein (CREB) that stimulates CRF expression as a transcription factor 27 ; (5) sex hormones, involving estrogen-receptors (ESR) 1 and 2 and androgen-receptor (AR), stimulating and inhibiting CRF gene expression, respectively 28,29 ; (6) the powerful CRF-stimulating proinflammatory cytokines such as interleukin 1-b (IL1b) that is produced by glial cells and PVN neurons, 30 and tumor necrosis factor-a (TNFa), a circulating state marker for depression 31 that is also produced by glial cells 32 ;…”

Section: Introductionmentioning

confidence: 99%

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances

et al. 2008

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Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-b and tumor necrosis factor-a, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. We hypothesized that, in depression, the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis are upregulated, whereas the transcript levels of the genes involved in the inhibition of the HPA axis are downregulated. We performed laser microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-a, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF neurons was decreased significantly. These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA axis in depression.

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Successful antidepressant therapy restores the disturbed interplay between TNF-alpha system and HPA axis

Cited by 32 publications

References 0 publications

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

Inflammation: a mechanism of depression?

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances

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