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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, Krishnan KR et al. Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry 2005; 58: 175–189.
Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of major depression. Trend Immun 2006; 27: 24–31.
Quan N, Stern EL, Whiteside MB, Herkenham M . Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J Neuroimmunol 1999; 93: 72–80.
Van Dam AM, Bol JG, Gaykema RP, Goehler LE, Maier SF, Watkins LR et al. Vagotomy does not inhibit high dose lipopolysaccharide-induced interleukin-1beta immunoreactivity in rat brain and pituitary gland. Neurosci Lett 2000; 285: 169–172.
Yirmiya R . Endotoxin produces a depressive-like episode in rats. Brain Res 1996; 711: 163–174.
Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58: 445–452.
Spath-Schwalbe E, Hansen K, Schmidt F, Schrezenmeier H, Marshall L, Burger K et al. Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. J Clin Endocrinol Metab 1998; 83: 1573–1579.
Bluthe RM, Dantzer R, Kelley KW . Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Res 1992; 573: 318–320.
Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006; 367: 29–35.
Gisslinger H, Svoboda T, Clodi M, Gilly B, Ludwig H, Havelec L et al. Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro. Neuroendocrinol 1993; 57: 489–495.
Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH . Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry 2003; 160: 1342–1345.
Muller H, Hammes E, Hiemke C, Hess G . Interferon-alpha-2-induced stimulation of ACTH and cortisol secretion in man. Neuroendocrinol 1991; 54: 499–503.
Shimizu H, Ohtani K, Sato N, Nagamine T, Mori M . Increase in serum interleukin-6, plasma ACTH and serum cortisol levels after systemic interferon-alpha administration. Endocr J 1995; 42: 551–556.
Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D′Hondt P et al. Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Res 1994; 54: 143–160.
Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M et al. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 2002; 22: 86–90.
Taylor JL, Grossberg SE . The effects of interferon-alpha on the production and action of other cytokines. Semin Oncol 1998; 25: 23–29.
Wichers MC, Kenis G, Koek GH, Robaeys G, Nicolson NA, Maes M . Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res 2007; 62: 207–214.
Raison CL, Demetrashvili M, Capuron L, Miller AH . Neuropsychiatric side effects of interferon-alpha: recognition and management. CNS Drugs 2005; 19: 1–19.
Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacol 2002; 26: 643–652.
Maddock C, Landau S, Barry K, Maulayah P, Hotopf M, Cleare AJ et al. Psychopathological symptoms during interferon-alpha and ribavirin treatment: effects on virologic response. Mol Psychiatry 2005; 10: 332–333.
Maddock C, Baita A, Orru MG, Sitzia R, Costa A, Muntoni E et al. Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms. J Psychopharmacol 2004; 18: 41–46.
Friebe A, Schwarz MJ, Schmid-Wendtner M, Volkenandt M, Schmidt F, Horn M et al. Pretreatment levels of sTNF-R1 and sIL-6R are associated with a higher vulnerability for IFN-alpha-induced depressive symptoms in patients with malignant melanoma. J Immunother 2007; 30: 333–337.
Matthews K, Schwartz J, Cohen S, Seeman T . Diurnal cortisol decline is related to coronary calcification: CARDIA study. Psychosom Med 2006; 68: 657–661.
Ticher A, Haus E, Ron IG, Sackett-Lundeen L, Ashkenazi IE . The pattern of hormonal circadian time structure (acrophase) as an assessor of breast-cancer risk. Int J Cancer 1996; 65: 591–593.
Rosmond R, Bjorntorp P . The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke. J Intern Med 2000; 247: 188–197.
Abercrombie HC, Giese-Davis J, Sephton S, Epel ES, Turner-Cobb JM, Spiegel D . Flattened cortisol rhythms in metastatic breast cancer patients. Psychoneuroendocrinol 2004; 29: 1082–1092.
Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D . Diurnal cortisol rhythm as a predictor of breast cancer survival. J Nat Cancer Inst 2000; 92: 994–1000.
Rich T, Innominato PF, Boerner J, Mormont MC, Iacobelli S, Baron B et al. Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clin Cancer Res 2005; 11: 1757–1764.
Nijm J, Kristenson M, Olsson AG, Jonasson L . Impaired cortisol response to acute stressors in patients with coronary disease. Implications for inflammatory activity. J Intern Med 2007; 262: 375–384.
Deuschle M, Schweiger U, Weber B, Gotthardt U, Korner A, Schmider J et al. Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls. J Clin Endocrinol Metab 1997; 82: 234–238.
Giese-Davis J, Sephton SE, Abercrombie HC, Duran RE, Spiegel D . Repression and high anxiety are associated with aberrant diurnal cortisol rhythms in women with metastatic breast cancer. Health Psychol 2004; 23: 645–650.
Bower JE, Ganz PA, Dickerson SS, Petersen L, Aziz N, Fahey JL . Diurnal cortisol rhythm and fatigue in breast cancer survivors. Psychoneuroendocrinol 2005; 30: 92–100.
Folstein MF, Folstein SE, McHugh PR . ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.
First MB, Spitzer RL, Gibbon M, Williams JB . Structured Clinical Interview for DSM-IV. American Psychiatric Press: Washington DC, 1997.
Majer M, Wellberg LAM, Capuron L, Pagnoni G, Raison CL, Miller AH . IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C. Brain Behav Immun 2008 (in press).
Montgomery SA, Asberg M . A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.
Smets EM, Garssen B, Bonke B, De Haes JC . The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995; 39: 315–325.
Stein KD, Jacobsen PB, Blanchard CM, Thors C . Further validation of the multidimensional fatigue symptom inventory-short form. J Pain Sympt Manage 2004; 27: 14–23.
Wichers MC, Koek GH, Robaeys G, Praamstra AJ, Maes M . Early increase in vegetative symptoms predicts IFN-alpha-induced cognitive-depressive changes. Psychol Med 2005; 35: 433–441.
Stone AA, Schwartz JE, Smyth J, Kirschbaum C, Cohen S, Hellhammer D et al. Individual differences in the diurnal cycle of salivary free cortisol: a replication of flattened cycles for some individuals. Psychoneuroendocrinol 2001; 26: 295–306.
Alesci S, Martinez PE, Kelkar S, Ilias I, Ronsaville DS, Listwak SJ et al. Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab 2005; 90: 2522–2530.
Adam EK, Gunnar MR . Relationship functioning and home and work demands predict individual differences in diurnal cortisol patterns in women. Psychoneuroendocrinol 2001; 26: 189–208.
Polk DE, Cohen S, Doyle WJ, Skoner DP, Kirschbaum C . State and trait affect as predictors of salivary cortisol in healthy adults. Psychoneuroendocrinol 2005; 30: 261–272.
Barnett RC, Steptoe A, Gareis KC . Marital-role quality and stress-related psychobiological indicators. Ann Behav Med 2005; 30: 36–43.
Van Cauter E, Leproult R, Plat L . Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 2000; 284: 861–868.
Plat L, Leproult R, L′Hermite-Baleriaux M, Fery F, Mockel J, Polonsky KS et al. Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning. J Clin Endocrinol Metab 1999; 84: 3082–3092.
Joynt KE, Whellan DJ, O’Connor CM . Depression and cardiovascular disease: mechanisms of interaction. Biol Psychiatry 2003; 54: 248–261.
Willerson JT, Ridker PM . Inflammation as a cardiovascular risk factor. Circulation 2004; 109: II2–I10.
Ridker PM, Buring JE, Cook NR, Rifai N . C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003; 107: 391–397.
Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352: 20–28.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM . C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327–334.
Pitsavos C, Tampourlou M, Panagiotakos DB, Skoumas Y, Chrysohoou C . Association between low-grade system inflammation and type 2 diabetes mellitus among men and women from the ATTICA Study. Rev Diab Stud 2007; 4: 98–104.
Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G . Inflammation and cancer: how hot is the link? Biochem Pharmacol 2006; 72: 1605–1621.
Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W . Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 1987; 238: 522–524.
Besedovsky HO, del Rey A . Immune-neuro-endocrine interactions: facts and hypotheses. Endocr Rev 1996; 17: 64–102.
Pace TW, Hu F, Miller AH . Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 2007; 21: 9–19.
Pariante CM, Pearce BD, Pisell TL, Sanchez CI, Po C, Su C et al. The proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function. Endocrinol 1999; 140: 4359–4366.
Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S . Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med 2006; 166: 1756–1762.
Opp MR, Obal Jr F, Krueger JM . Interleukin 1 alters rat sleep: temporal and dose-related effects. Am J Physiol 1991; 260: R52–R58.
Spath-Schwalbe E, Lange T, Perras B, Fehm HL, Born J . Interferon-alpha acutely impairs sleep in healthy humans. Cytokine 2000; 12: 518–521.
Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Follett H, Kales A et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 2004; 89: 2119–2126.
Redwine L, Hauger RL, Gillin JC, Irwin M . Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans. J Clin Endocrinol Metab 2000; 85: 3597–3603.
Spiegel K, Leproult R, Van Cauter E . Impact of sleep debt on metabolic and endocrine function. Lancet 1999; 354: 1435–1439.
Ogawa Y, Kanbyashi T, Yano T, Sawaishi Y, Saito Y, Shimizu T . Cerebrospinal fluid-orexin decreases during intraventricular a-interferon therapy of patients with subacute sclerosing panencephalitis. Sleep Biol Rhyth 2003; 1: 143–145.
Ohdo S, Koyanagi S, Suyama H, Higuchi S, Aramaki H . Changing the dosing schedule minimizes the disruptive effects of interferon on clock function. Nature Med 2001; 7: 356–360.
Fernandez-Real JM, Lainez B, Vendrell J, Rigla M, Castro A, Penarroja G et al. Shedding of TNF-alpha receptors, blood pressure, and insulin sensitivity in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 2002; 282: E952–E959.
Bower JE, Ganz PA, Aziz N, Fahey JL . Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med 2002; 64: 604–611.
Dome P, Teleki Z, Rihmer Z, Peter L, Dobos J, Kenessey I et al. Circulating endothelial progenitor cells and depression: a possible novel link between heart and soul. Mol Psychiatry 2008; epub: 1–9.
Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D . Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 1992; 175: 323–329.
Schroder J, Stuber F, Gallati H, Schade FU, Kremer B . Pattern of soluble TNF receptors I and II in sepsis. Infection 1995; 23: 143–148.
Ice GH . Factors influencing cortisol level and slope among community dwelling older adults in Minnesota. J Cross Cult Gerontol 2005; 20: 91–108.
Daniel M, Moore DS, Decker S, Belton L, DeVellis B, Doolen A et al. Associations among education, cortisol rhythm, and BMI in blue-collar women. Obesity 2006; 14: 327–335.
Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS et al. Paroxetine for the prevention of depression induced by high-dose interferon alpha. N Engl J Med 2001; 344: 961–966.
Licinio J, Mantzoros C, Negrao AB, Cizza G, Wong ML, Bongiorno PB et al. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nature Med 1997; 3: 575–579.
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
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.
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2008.58
Keywords
This article is cited by
-
Symptoms of Liver Disease During Tenofovir Therapy With or Without Peginterferon: Results from the Hepatitis B Research Network Immune Active Trial
Digestive Diseases and Sciences (2023)
-
What we have to know about corticosteroids use during Sars-Cov-2 infection
Journal of Endocrinological Investigation (2021)
-
What does plasma CRP tell us about peripheral and central inflammation in depression?
Molecular Psychiatry (2020)
-
Behavioral Symptoms of Anxiety and Depression and Brain Monoamine Contents in Rats after Chronic Intranasal Administration of Interferon-α
Neuroscience and Behavioral Physiology (2018)
-
Pathogen–Host Defense in the Evolution of Depression: Insights into Epidemiology, Genetics, Bioregional Differences and Female Preponderance
Neuropsychopharmacology (2017)