Systemic inflammation is accompanied by profound behavioral and mood changes that resemble symptoms of depression. Findings in animals suggest that pro-inflammatory cytokines released by activated immune cells in the periphery evoke these behavioral symptoms by driving inflammatory changes in the brain. However, experimental data in humans are lacking. Here we demonstrate in healthy male volunteers (10 endotoxin treated, 8 placebo treated) that intravenous administration of low-dose endotoxin (0.8 ng/kg body weight), a prototypical pathogen-associated molecular pattern that activates the innate immune system, not only induces a significant increase in peripheral blood cytokine concentrations (that is, tumor necrosis factor-α, interleukin (IL)-6, IL-10) but also results, with some latency, in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF). Moreover, we found a strong association between the endotoxin-induced increase of IL-6 in the CSF and the severity of mood impairment, with larger increases in CSF IL-6 concentration followed by a greater deterioration in mood. Taken together, these findings suggest that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration, identifying IL-6 as a potential therapeutic target in mood disorders.
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Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB . Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2015; 2: 258–270.
Haroon E, Raison CL, Miller AH . Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37: 137–162.
Rosenblat JD, Cha DS, Mansur RB, McIntyre RS . Inflamed moods: a review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry 2014; 53: 23–34.
Miller AH, Raison CL . The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16: 22–34.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446–457.
Howren MB, Lamkin DM, Suls J . Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71: 171–186.
Modabbernia A, Taslimi S, Brietzke E, Ashrafi M . Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 2013; 74: 15–25.
Miller AH, Maletic V, Raison CL . Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741.
Lindqvist D, Janelidze S, Hagell P, Erhardt S, Samuelsson M, Minthon L et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry 2009; 66: 287–292.
Matcham F, Rayner L, Steer S, Hotopf M . The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology 2013; 52: 2136–2148.
Fleming P, Roubille C, Richer V, Starnino T, McCourt C, McFarlane A et al. Effect of biologics on depressive symptoms in patients with psoriasis: a systematic review. J Eur Acad Dermatol Venereol 2015; 29: 1063–1070.
Graff LA, Walker JR, Bernstein CN . Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflamm Bowel Dis 2009; 15: 1105–1118.
Patten SB, Beck CA, Williams JV, Barbui C, Metz LM . Major depression in multiple sclerosis: a population-based perspective. Neurology 2003; 61: 1524–1527.
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.
Abbott R, Whear R, Nikolaou V, Bethel A, Coon JT, Stein K et al. Tumour necrosis factor-α inhibitor therapy in chronic physical illness: a systematic review and meta-analysis of the effect on depression and anxiety. J Psychosom Res 2015; 79: 175–184.
Capuron L, Hauser P, Hinze-Selch D, Miller AH, Neveu PJ . Treatment of cytokine-induced depression. Brain Behav Immun 2002; 16: 575–580.
Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.
Dowell NG, Cooper EA, Tibble J, Voon V, Critchley HD, Cercignani M et al. Acute changes in striatal microstructure predict the development of interferon-alpha induced fatigue. Biol Psychiatry 2016; 79: 320–328.
Maes M, Berk M, Goehler L, Song C, Anderson G, Galecki P et al. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 2012; 10: 66.
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW . From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46–56.
Quan N, Banks WA . Brain-immune communication pathways. Brain Behav Immun 2007; 21: 727–735.
Goehler LE, Gaykema RP, Hansen MK, Anderson K, Maier SF, Watkins LR . Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci 2000; 85: 49–59.
Banks WA . The blood-brain barrier in psychoneuroimmunology. Neurol Clin 2006; 24: 413–419.
Vitkovic L, Konsman JP, Bockaert J, Dantzer R, Homburger V, Jacque C . Cytokine signals propagate through the brain. Mol Psychiatry 2000; 5: 604–615.
Engler H, Doenlen R, Engler A, Riether C, Prager G, Niemi MB et al. Acute amygdaloid response to systemic inflammation. Brain Behav Immun 2011; 25: 1384–1392.
Poon DC, Ho YS, Chiu K, Wong HL, Chang RC . Sickness: from the focus on cytokines, prostaglandins, and complement factors to the perspectives of neurons. Neurosci Biobehav Rev 2015; 57: 30–45.
Schedlowski M, Engler H, Grigoleit JS . Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. Brain Behav Immun 2014; 35: 1–8.
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.
Engler H, Benson S, Wegner A, Spreitzer I, Schedlowski M, Elsenbruch S . Men and women differ in inflammatory and neuroendocrine responses to endotoxin but not in the severity of sickness symptoms. Brain Behav Immun 2016; 52: 18–26.
Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR . Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 2010; 68: 748–754.
Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR . Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun 2010; 24: 558–563.
DellaGioia N, Hannestad J . A critical review of human endotoxin administration as an experimental paradigm of depression. Neurosci Biobehav Rev 2010; 34: 130–143.
Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA 2015; 112: 12468–12473.
Zigmond AS, Snaith RP . The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361–370.
Laux L, Hock M, Bergner-Köther R, Hodapp V, Renner K-H, Merzbacher G. The State-Trait Anxiety Depression Inventory (STADI). Hogrefe: Göttingen, Germany, 2013.
Faul F, Erdfelder E, Lang AG, Buchner AG . *Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007; 39: 175–191.
Raison CL, Borisov AS, Majer M, Drake DF, Pagnoni G, Woolwine BJ et al. Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol Psychiatry 2009; 65: 296–303.
Kakizaki Y, Watanobe H, Kohsaka A, Suda T . Temporal profiles of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in the plasma and hypothalamic paraventricular nucleus after intravenous or intraperitoneal administration of lipopolysaccharide in the rat: estimation by push-pull perfusion. Endocr J 1999; 46: 487–496.
Datta SC, Opp MR . Lipopolysaccharide-induced increases in cytokines in discrete mouse brain regions are detectable using Luminex xMAP technology. J Neurosci Meth 2008; 175: 119–124.
Erickson MA, Banks WA . Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. Brain Behav Immun 2011; 25: 1637–1648.
Banks WA . The blood-brain barrier in neuroimmunology: Tales of separation and assimilation. Brain Brain Behav Immun 2015; 44: 1–8.
Vallieres L, Rivest S . Regulation of the genes encoding interleukin-6, its receptor, and gp130 in the rat brain in response to the immune activator lipopolysaccharide and the proinflammatory cytokine interleukin-1beta. J Neurochem 1997; 69: 1668–1683.
LeMay LG, Vander AJ, Kluger MJ . Role of interleukin-6 in fever in rats. Am J Physiol 1990; 258: R798–R803.
Reyes TM, Fabry Z, Coe CL . Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli. Brain Res 1999; 851: 215–220.
Marques F, Sousa JC, Coppola G, Falcao AM, Rodrigues AJ, Geschwind DH et al. Kinetic profile of the transcriptome changes induced in the choroid plexus by peripheral inflammation. J Cereb Blood Flow Metab 2009; 29: 921–932.
Grigoleit JS, Kullmann JS, Wolf OT, Hammes F, Wegner A, Jablonowski S et al. Dose-dependent effects of endotoxin on neurobehavioral functions in humans. PloS One 2011; 6: e28330.
Wegner A, Elsenbruch S, Maluck J, Grigoleit JS, Engler H, Jager M et al. Inflammation-induced hyperalgesia: effects of timing, dosage, and negative affect on somatic pain sensitivity in human experimental endotoxemia. Brain Behav Immun 2014; 41: 46–54.
Lasselin J, Elsenbruch S, Lekander M, Axelsson J, Karshikoff B, Grigoleit JS et al. Mood disturbance during experimental endotoxemia: predictors of state anxiety as a psychological component of sickness behavior. Brain Behav Immun 2016; 57: 30–37, in press).
Wright CE, Strike PC, Brydon L, Steptoe A . Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun 2005; 19: 345–350.
Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD . Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 2009; 66: 407–414.
Sasayama D, Hattori K, Wakabayashi C, Teraishi T, Hori H, Ota M et al. Increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and those with major depressive disorder. J Psychiatr Res 2013; 47: 401–406.
Goldsmith DR, Rapaport MH, Miller BJ . A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 2016; 21: 1696–1709.
Valkanova V, Ebmeier KP, Allan CL . CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord 2013; 150: 736–744.
Venkiteshwaran A . Tocilizumab. mAbs 2009; 1: 432–438.
Strand V, Singh JA . Newer biological agents in rheumatoid arthritis: impact on health-related quality of life and productivity. Drugs 2010; 70: 121–145.
Seiler W, Müller H, Hiemke C . Interleukin-6 in plasma collected with an indwelling cannula reflects local, not systemic, concentrations. Clin Chem 1994; 40: 1778–1779.
Gudmundsson A, Ershler WB, Goodman B, Lent SJ, Barczi S, Carnes M . Serum concentrations of interleukin-6 are increased when sampled through an indwelling venous catheter. Clin Chem 1997; 43: 2199–2201.
Haack M, Reichenberg A, Kraus T, Schuld A, Yirmiya R, Pollmächer T . Effects of an intravenous catheter on the local production of cytokines and soluble cytokine receptors in healthy men. Cytokine 2000; 12: 694–698.
Llano DA, Li J, Warring JF, Ellis T, Devanarayan V, Witte DG, Lenz RA . Cerebrospinal fluid cytokine dynamics differ between Alzheimer disease patients and elderly controls. Alzheimer Dis Assoc Disord 2012; 26: 322–328.
Kessler R, McGonagle K, Zhao S, Nelson C, Hughes M, Eshleman S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51: 8–19.
We thank Ursula Brecklinghaus and Alexandra Kornowski for excellent technical assistance and Bettina Löschner and Dr Ingo Spreitzer (Paul-Ehrlich-Institute, Langen, Germany) for endotoxin safety testing. This work was supported by an internal research grant from the Medical Faculty of the University of Duisburg-Essen (IFORES) awarded to HE.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Engler, H., Brendt, P., Wischermann, J. et al. Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms. Mol Psychiatry 22, 1448–1454 (2017). https://doi.org/10.1038/mp.2016.264
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