Constant Darkness Induces IL-6-Dependent Depression-Like Behavior through the NF- B Signaling Pathway

Monje, Francisco J.; Cabatic, Maureen; Divisch, Isabella; Kim, Eun-Jung; Herkner, Kurt; Binder, Bernd R.; Pollak, Daniela D.

doi:10.1523/jneurosci.1537-11.2011

Cited by 160 publications

(140 citation statements)

References 58 publications

(73 reference statements)

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“…This evidence builds upon a previously study that demonstrated an antidepressant-like response to acute stress in constitutive IL-6 knockouts and suggests that leukocyte-derived sources of IL-6 may be critical in mediating these behavioral effects (34). Our results are interesting in light of recent studies showing that social defeat stress induces downstream inflammatory signaling pathways, such as NFkB (26,(35)(36)(37), and increases monocyte trafficking (29) throughout a number of CNS structures known to control depression and anxiety behavior. It will be important for future studies to define the brain regions and molecular pathways induced by stress-responsive IL-6 from leukocytes that mediate adverse behavioral responses to chronic stress.…”

Section: Significancesupporting

confidence: 84%

“…Both in vivo and ex vivo IL-6 levels in response to stimulation were the strongest predictor of the behavioral response to a subsequent social stress. Although previous studies have identified elevated serum IL-6 and circulating leukocytes in stress disorders, this generally followed either depression diagnosis in humans (4,25) or controlled stress exposure in rodents (26,27). To our knowledge, this is the first study to show that the IL-6 response before social stress exposure can predict individual differences in vulnerability to a subsequent social stressor.…”

Section: Significancementioning

confidence: 87%

See 1 more Smart Citation

Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

Hodes

Pfau

Leboeuf

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

586

506

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Significance Depression and anxiety have been linked to increased inflammation. However, we do not know if inflammatory status predates onset of disease or whether it contributes to depression symptomatology. We report preexisting individual differences in the peripheral immune system that predict and promote stress susceptibility. Replacing a stress-naive animal’s peripheral immune system with that of a stressed animal increases susceptibility to social stress including repeated social defeat stress (RSDS) and witness defeat (a purely emotional form of social stress). Depleting the cytokine IL-6 from the whole body or just from leukocytes promotes resilience, as does sequestering IL-6 outside of the brain. These studies demonstrate that the emotional response to stress can be generated or blocked in the periphery, and offer a potential new form of treatment for stress disorders.

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Section: Significancesupporting

confidence: 84%

Section: Significancementioning

confidence: 87%

Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

Hodes

Pfau

Leboeuf

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

586

506

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“…It has previously been shown that p53 mutant mice lacking functional CRY proteins are more susceptible to TNF-α-initiated apoptosis through NF-κB activation (39). Monje et al had reported that depression like behavior in mice induced by constant darkness is associated with increased levels of IL-6 in plasma and hippocampus mediated through NF-κB signaling pathway (40). Interestingly, NF-κB has been shown to play a role in metabolic adaptation both in normal and also in cancer cells by regulation of mitochondrial oxidative phosphorylation (41), and the current finding will suggest an additional CRY-NF-κB-mediated pathway in metabolic adaptation of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines

Narasimamurthy

Hatori

Nayak

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

344

264

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Chronic sleep deprivation perturbs the circadian clock and increases susceptibility to diseases such as diabetes, obesity, and cancer. Increased inflammation is one of the common underlying mechanisms of these diseases, thus raising a hypothesis that circadianoscillator components may regulate immune response. Here we show that absence of the core clock component protein cryptochrome (CRY) leads to constitutive elevation of proinflammatory cytokines in a cell-autonomous manner. We observed a constitutive NF-κB and protein kinase A (PKA) signaling activation in Cry1 −/− ; Cry2 −/− cells. We further demonstrate that increased phosphorylation of p65 at S276 residue in Cry1 −/− ;Cry2 −/− cells is due to increased PKA signaling activity, likely induced by a significantly high basal level of cAMP, which we detected in these cells. In addition, we report that CRY1 binds to adenylyl cyclase and limits cAMP production. Based on these data, we propose that absence of CRY protein(s) might release its (their) inhibition on cAMP production, resulting in elevated cAMP and increased PKA activation, subsequently leading to NF-κB activation through phosphorylation of p65 at S276. These results offer a mechanistic framework for understanding the link between circadian rhythm disruption and increased susceptibility to chronic inflammatory diseases.biological clock | immune system I n response to the rotation of the earth, many of the mammalian physiological processes such as sleep-wake cycle and feeding pattern undergo an ∼24-h oscillation referred as the circadian clock. Circadian oscillation helps organisms anticipate and adapt to predictable daily changes in the environment. The hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian oscillator, which controls behaviors. At molecular level, the circadian oscillator is based on a cell-autonomous transcription-translation feedback loop, in which transcriptional activators circadian locomotor output cycles kaput (CLOCK)/brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like (BMAL)1 activate the expression of Cryptochrome (Cry) and Period (Per), in turn their protein products repress BMAL1 and CLOCK activity, thus producing Cry and Per expression rhythms (1, 2). Reverse orientation c-erb (REV-ERB)s and RAR-related orphan receptor (ROR)s also participate in the rhythmic transcriptional activity of the molecular oscillator (3). Molecular components of the circadian clock network are conserved in the SCN and also in peripheral cells. The oscillator uses direct and indirect mechanisms to impose rhythms and regulate several physiological processes, such as rest-activity cycle, endocrine system, and metabolism (4).Sleep loss or chronic sleep deprivation disrupts the circadian rhythm. It has been reported that people exposed to constant circadian disruption, such as shift-workers, show increased incidence of chronic diseases such as diabetes, obesity, and also cancer (5-7). Chronic inflammation is one of the important pathogenic features of these di...

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“…For instance, long-term light deprivation in the constant darkness paradigm induces elevated levels of IL-6 and IL1-R1 (interleukin 1 receptor, type I) in the hippocampus through the NF-κB signaling pathway, known to play a vital role in the cellular expression of pro-inflammatory genes [47] . Moreover, the expression of pro-inflammatory cytokines is induced by a high oxidative-stress status.…”

Section: Can the Brain Produce Cytokines?mentioning

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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Constant Darkness Induces IL-6-Dependent Depression-Like Behavior through the NF- B Signaling Pathway

Cited by 160 publications

References 58 publications

Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines

Inflammation: a mechanism of depression?

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