Article

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

ABSTRACT

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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    • "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). "

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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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