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Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms

Molecular Psychiatry volume 22, pages 1448–1454 (2017)Cite this article

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Abstract

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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References

  1. 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.

    Article  Google Scholar 

  2. Haroon E, Raison CL, Miller AH . Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37: 137–162.

    Article  CAS  Google Scholar 

  3. 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.

    Article  CAS  Google Scholar 

  4. Miller AH, Raison CL . The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16: 22–34.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Article  Google Scholar 

  13. Patten SB, Beck CA, Williams JV, Barbui C, Metz LM . Major depression in multiple sclerosis: a population-based perspective. Neurology 2003; 61: 1524–1527.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. 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.

    Article  Google Scholar 

  16. Capuron L, Hauser P, Hinze-Selch D, Miller AH, Neveu PJ . Treatment of cytokine-induced depression. Brain Behav Immun 2002; 16: 575–580.

    Article  CAS  Google Scholar 

  17. Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.

    Article  CAS  Google Scholar 

  18. 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.

    Article  CAS  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. Quan N, Banks WA . Brain-immune communication pathways. Brain Behav Immun 2007; 21: 727–735.

    Article  CAS  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. Banks WA . The blood-brain barrier in psychoneuroimmunology. Neurol Clin 2006; 24: 413–419.

    Article  Google Scholar 

  24. Vitkovic L, Konsman JP, Bockaert J, Dantzer R, Homburger V, Jacque C . Cytokine signals propagate through the brain. Mol Psychiatry 2000; 5: 604–615.

    Article  CAS  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

  29. 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.

    Article  CAS  Google Scholar 

  30. 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.

    Article  CAS  Google Scholar 

  31. 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.

    Article  Google Scholar 

  32. DellaGioia N, Hannestad J . A critical review of human endotoxin administration as an experimental paradigm of depression. Neurosci Biobehav Rev 2010; 34: 130–143.

    Article  CAS  Google Scholar 

  33. 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.

    Article  CAS  Google Scholar 

  34. Zigmond AS, Snaith RP . The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361–370.

    Article  CAS  Google Scholar 

  35. 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.

  36. 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.

    Article  Google Scholar 

  37. 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.

    Article  CAS  Google Scholar 

  38. 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.

    Article  CAS  Google Scholar 

  39. 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.

    Article  CAS  Google Scholar 

  40. 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.

    Article  CAS  Google Scholar 

  41. Banks WA . The blood-brain barrier in neuroimmunology: Tales of separation and assimilation. Brain Brain Behav Immun 2015; 44: 1–8.

    Article  CAS  Google Scholar 

  42. 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.

    Article  CAS  Google Scholar 

  43. LeMay LG, Vander AJ, Kluger MJ . Role of interleukin-6 in fever in rats. Am J Physiol 1990; 258: R798–R803.

    CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  Google Scholar 

  45. 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.

    Article  CAS  Google Scholar 

  46. 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.

    Article  CAS  Google Scholar 

  47. 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.

    Article  CAS  Google Scholar 

  48. 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).

    Article  Google Scholar 

  49. Wright CE, Strike PC, Brydon L, Steptoe A . Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun 2005; 19: 345–350.

    Article  CAS  Google Scholar 

  50. 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.

    Article  Google Scholar 

  51. 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.

    Article  Google Scholar 

  52. 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.

    Article  CAS  Google Scholar 

  53. 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.

    Article  CAS  Google Scholar 

  54. Venkiteshwaran A . Tocilizumab. mAbs 2009; 1: 432–438.

    Article  Google Scholar 

  55. Strand V, Singh JA . Newer biological agents in rheumatoid arthritis: impact on health-related quality of life and productivity. Drugs 2010; 70: 121–145.

    Article  CAS  Google Scholar 

  56. 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.

    CAS  PubMed  Google Scholar 

  57. 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.

    CAS  PubMed  Google Scholar 

  58. 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.

    Article  CAS  Google Scholar 

  59. 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.

    Article  CAS  Google Scholar 

  60. 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.

    Article  CAS  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    H Engler, R Röhling, S Benson & M Schedlowski

  2. Clinic for Anesthesiology and Intensive Care Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    P Brendt, J Wischermann & J Peters

  3. Department of Orthopedic and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    A Wegner

  4. Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    T Schoemberg

  5. Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland

    U Meyer

  6. Department of Neurology, St Josef-Hospital, Ruhr University, Bochum, Germany

    R Gold

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  1. H Engler
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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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