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

Molecular Psychiatry volume 15, pages 535–547 (2010)Cite this article

Abstract

Interferon (IFN)-α has been used to investigate pathways by which innate immune cytokines influence the brain and behavior. Accordingly, the impact of IFN-α on diurnal secretion of hypothalamic–pituitary–adrenal (HPA) axis hormones was assessed in 33 patients eligible for treatment with IFN-α plus ribavirin for hepatitis C. In addition, the relationship between IFN-α-induced HPA axis changes and proinflammatory cytokines and behavior was examined. Plasma ACTH and cortisol as well as tumor necrosis factor (TNF)-α, 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-α/ribavirin (n=20). Plasma IFN-α 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-α/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-α, TNF-α and soluble TNF-α 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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Acknowledgements

This study was funded by grants from the National Institute of Mental Health (K05 MH069124, K23 MH064619, R01 MH070553 and R01 HL073921) an NIH/NCRR General Clinical Research Center grant (M01 RR00039) and the Centers for Disease Control and Prevention.

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  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    C L Raison, A S Borisov, B J Woolwine, Breanne Massung, G Vogt & A H Miller

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  1. C L Raison
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Correspondence to C L Raison.

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CL Raison has served as a speaker for Lilly and Wyeth and as a consultant or an advisory board member for Schering-Plough, Wyeth, Lilly and Centocor; AS Borisov, BJ Woolwine, B Massung and G Vogt have nothing to declare; AH Miller has served as a consultant or an advisory board member for Schering-Plough and Centocor, and has received research funding from Janssen/Johnson and Johnson, GlaxoSmithKline and Schering-Plough.

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Raison, C., Borisov, A., Woolwine, B. et al. Interferon-α effects on diurnal hypothalamic–pituitary–adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry 15, 535–547 (2010). https://doi.org/10.1038/mp.2008.58

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