Interferon-α effects on diurnal hypothalamic pituitary-adrenal axis activity: Relationship with proinflammatory cytokines and behavior

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
Molecular Psychiatry (Impact Factor: 14.5). 05/2010; 15(5):535-47. DOI: 10.1038/mp.2008.58
Source: PubMed


Interferon (IFN)-alpha has been used to investigate pathways by which innate immune cytokines influence the brain and behavior. Accordingly, the impact of IFN-alpha on diurnal secretion of hypothalamic-pituitary-adrenal (HPA) axis hormones was assessed in 33 patients eligible for treatment with IFN-alpha plus ribavirin for hepatitis C. In addition, the relationship between IFN-alpha-induced HPA axis changes and proinflammatory cytokines and behavior was examined. Plasma ACTH and cortisol as well as tumor necrosis factor (TNF)-alpha, interleukin-6 and their soluble receptors, were measured hourly between 0900 and 2100 hours at baseline and following approximately 12 weeks of either no treatment (n=13) or treatment with IFN-alpha/ribavirin (n=20). Plasma IFN-alpha was also measured at each visit. Depression and fatigue were assessed using the Montgomery-Asberg depression rating scale and the multidimensional fatigue inventory. Compared to no treatment, IFN-alpha/ribavirin administration was associated with significant flattening of the diurnal ACTH and cortisol slope and increased evening plasma ACTH and cortisol concentrations. Flattening of the cortisol slope and increases in evening cortisol were correlated with increases in depression (r=0.38, P<0.05 and r=0.36, P<0.05, respectively) and fatigue (r=0.43, P<0.05 and r=0.49, P<0.01, respectively). No relationship was found between immune and HPA axis measures, although increases in plasma IFN-alpha, TNF-alpha and soluble TNF-alpha receptor2 were independently correlated with behavioral endpoints. These data indicate that chronic exposure to innate immune cytokines may contribute to the altered diurnal HPA axis activity and behavior found in medically ill individuals. However, given the lack of correlation between HPA axis and immune measures, the mechanism by which chronic cytokine exposure influences HPA axis function remains to be determined.

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Available from: Charles L Raison, Jan 16, 2014
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    • "Cytokine-induced alterations within the central nervous system (CNS) may depend on various mechanisms, including the passage of cytokines through leaky regions of the blood-brain barrier and activation of nervous pathways (Anisman, 2009). A high concentration of proinflammatory cytokines with activity in the CNS may modulate monoamine neurotransmission (Raison et al., 2009), alter the glucocorticoid axis and dysregulate apoptotic mechanisms (Cai et al., 2005; Asnis and De La Garza, 2006; Raison et al., 2010a), which are factors related with the onset of clinical depression (Anisman, 2009). "
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    ABSTRACT: Background: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality and functional genetic variants associated to cytokine-induced depression. Methods: We recruited 344 Caucasian outpatients with chronic hepatitis C initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline, 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ) and the Hospital Anxiety and Depression Scale (HADS) and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF) and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. Results: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy–Weinberg equilibrium. Older age (p=0.018, hazard ratio per 5 years=1.21), presence of depression history (p=0.0001, HR=2.38), and subthreshold depressive symptoms at baseline (p=0.005, HR=1.13) increased the risk of IFN-induced depression. So too did TCI-personality traits, with high scores on fatigability (p=0.0037, HR=1.17), impulsiveness (p=0.0200 HR= 1.14), disorderliness (p=0.0339, HR=1.11), and low scores on extravagance (p=0.0040, HR=0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR=3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR=3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p= 0.0436, HR=1.88) and BDNF genes (Val/Val genotype: p=0.0453, HR=0.55) were associated with depression. Conclusions: The results of the study support that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders. Key words
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    • "We therefore explored effects of aging on the glutamate response to IFN-alpha in patients with hepatitis C virus (HCV) and determined whether these effects were associated with alterations in inflammatory markers and behaviors previously shown to be altered in IFN-alpha-treated patients including tumor necrosis factor (TNF) and its soluble receptor sTNFR2, motivation, and motor activity (Capuron et al., 2012; Majer et al., 2008; Raison et al., 2010). "

    Full-text · Article · Oct 2015 · Brain Behavior and Immunity
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    • "Moreover, elevated plasma levels of TNF-í µí»¼ are associated with treatment resistance to conventional antidepressants [15]. In hepatitis C patients that are chronically treated with interferon-í µí»¼, increased blood levels of TNF-í µí»¼ correlate with the development of depressive symptoms [16]. Furthermore, peripheral administration of anti-TNF-í µí»¼ antibodies improves depressed mood in patients suffering from psoriasis [17], Crohn's disease [18], and rheumatoid arthritis [19]. "
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    ABSTRACT: Clinical observations indicate that activation of the TNF-α system may contribute to the development of inflammation-associated depression. Here, we tested the hypothesis that systemic upregulation of TNF-α induces neuroinflammation and behavioral changes relevant to depression. We report that a single intraperitoneal injection of TNF-α in mice increased serum and brain levels of the proinflammatory mediators TNF-α, IL-6, and MCP-1, in a dose- and time-dependent manner, but not IL-1β. Protein levels of the anti-inflammatory cytokine IL-10 increased in serum but not in the brain. The transient release of immune molecules was followed by glial cell activation as indicated by increased astrocyte activation in bioluminescent Gfap-luc mice and elevated immunoreactivity against the microglial marker Iba1 in the dentate gyrus of TNF-α-challenged mice. Additionally, TNF-α-injected mice were evaluated in a panel of behavioral tests commonly used to study sickness and depressive-like behavior in rodents. Our behavioral data imply that systemic administration of TNF-α induces a strong sickness response characterized by reduced locomotor activity, decreased fluid intake, and body weight loss. Depressive-like behavior could not be separated from sickness at any of the time points studied. Together, these results demonstrate that peripheral TNF-α affects the central nervous system at a neuroimmune and behavioral level.
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