Low levels of circulating inflammatory cytokines—Do they affect human brain functions?
Abstract
Animal studies provide consistent evidence for the pivotal role of inflammatory cytokines in inducing sickness behavior during systemic infection and inflammation. Because depression in humans shows a considerable symptomatic overlap with sickness behavior, it has been hypothesized that cytokines are also involved in affective disorders. This view is supported by studies showing that therapeutic administration of inflammatory cytokines can induce typical major depression and by evidence that stimulated cytokine-release during experimental endotoxemia provokes transient deterioration in mood and memory. However, in these conditions, similar to the animal models of acute infections, huge amounts of cytokines produced in the periphery act on the brain. In contrast, during most clinical conditions where depression might involve cytokine actions, such as chronic infection and inflammation, only low amounts of cytokines are circulating. The present paper addresses the question whether and how low amounts of circulating cytokines act on the human brain. Evidence is presented that very low amounts of circulating cytokines are likely to influence brain functions, even under baseline conditions. It is also likely that low levels of cytokines affect the same brain function as high levels do. However, it is uncertain whether these effects go in the same direction. NonREM sleep, for example, is promoted by a slight increase in cytokine levels, but suppressed by prominent increases. Because no comparable data are available for mood and other brain functions, the answer to the question whether and how low circulating amounts of cytokines affect mood depends on further experimental studies.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
It is still unclear whether different doses of cytokines have similar effects on depression.
“It is still unclear, if the doses have similar effects on depression[74].”
From Neuroinflammation and cytokine abnormality in major depression: cause or consequence in that illness? (2016) · cites this paper as [74]
Low levels of peripheral cytokines have a similar effect on sleep-awake behaviors compared with a high dose of peripheral cytokines.
“Low levels of peripheral cytokines have a similar effect on sleep-awake behaviors compared with a high dose of peripheral cytokines[74].”
From Neuroinflammation and cytokine abnormality in major depression: cause or consequence in that illness? (2016) · cites this paper as [74]
Under physiological conditions cytokines have a beneficial role on learning and memory, e.g. by promoting long term potentiation (LTP), neural plasticity and neural excitability.
“Under physiological conditions cytokines have a beneficial role on learning and memory, e.g. by promoting long term potentiation (LTP), neural plasticity and neural excitability [3], [52], [53].”
From Dose-dependent effects of endotoxin on neurobehavioral functions in humans (2011) · cites this paper as [53]
Cites
The Relationship of Depression to Cardiovascular Disease: Epidemiology, Biology, and Treatment
Musselman, D. L., Evans, D. L., & Nemeroff, C. B. (1998) · Archives of General Psychiatry · doi:10.1001/archpsyc.55.7.580 · Cited by 1,532 · see citing works
Immunoregulatory Feedback Between Interleukin-1 and Glucocorticoid Hormones
Besedovsky, H., del Rey, A., Sorkin, E., & Dinarello, C. A. (1986) · Science · doi:10.1126/science.3014662 · Cited by 1,519 · see citing works
Cytokine-Associated Emotional and Cognitive Disturbances in Humans
Reichenberg, A., Yirmiya, R., Schuld, A., Kraus, T., Haack, M., Morag, A., & Pollmächer, T. (2001) · Archives of General Psychiatry · doi:10.1001/archpsyc.58.5.445 · Cited by 1,365 · see citing works
Self-citationRegulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action
TURNBULL, A. V., & RIVIER, C. L. (1999) · Physiological Reviews · doi:10.1152/physrev.1999.79.1.1 · Cited by 1,297 · see citing works
Fever: Role of Pyrogens and Cryogens
Kluger, M. J. (1991) · Physiological Reviews · doi:10.1152/physrev.1991.71.1.93 · Cited by 1,220 · see citing works
The macrophage theory of depression
Smith, R. S. (1991) · Medical Hypotheses · doi:10.1016/0306-9877(91)90272-z · Cited by 931 · see citing works
Cytokines and the nervous system II: actions and mechanisms of action
Rothwell, N. J., & Hopkins, S. J. (1995) · Trends in Neurosciences · doi:10.1016/0166-2236(95)93890-a · Cited by 922 · see citing works
Cytokine-induced sickness behavior: where do we stand?
Dantzer, R. (2001) · Brain, Behavior, and Immunity · doi:10.1006/brbi.2000.0613 · Cited by 862 · see citing works
Cytokines and the nervous system I: expression and recognition
Hopkins, S. J., & Rothwell, N. J. (1995) · Trends in Neurosciences · doi:10.1016/0166-2236(95)80029-2 · Cited by 793 · see citing works
Tumor necrosis factor in the heart
Meldrum, D. R. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.274.3.r577 · Cited by 747 · see citing works
Haack, M., Hinze‐Selch, D., Fenzel, T., Kraus, T., Kühn, M., Schuld, A., & Pollmächer, T. (1999) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(99)00021-7 · Cited by 329 · see citing works
Self-citationIllness, Cytokines, and Depression
YIRMIYA, R., POLLAK, Y., MORAG, M., REICHENBERG, A., BARAK, O., AVITSUR, R., SHAVIT, Y., OVADIA, H., WEIDENFELD, J., MORAG, A., et al. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb05412.x · Cited by 284 · see citing works
Self-citationSleep deprivation and human immune function
Dinges, D. F., Douglas, S. D., Hamarman, S., Zaugg, L., & Kapoor, S. C. (1995) · Advances in Neuroimmunology · doi:10.1016/0960-5428(95)00002-j · Cited by 234 · see citing works
Interleukin 1 alters rat sleep: temporal and dose-related effects
Opp, M. R., Obal, F., & Krueger, J. M. (1991) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1991.260.1.r52 · Cited by 232 · see citing works
THE ROLE OF TNF IN CARDIOVASCULAR DISEASE
Ferrari, R. (1999) · Pharmacological Research · doi:10.1006/phrs.1998.0463 · Cited by 180 · see citing works
Effects of antipsychotic drugs on cytokine networks
Pollmächer, T., Haack, M., Schuld, A., Kraus, T., & Hinze‐Selch, D. (2000) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(00)00032-7 · Cited by 180 · see citing works
Self-citationNocturnal plasma levels of cytokines in healthy men
Gudewill, S., Pollmächer, T., Vedder, H., Schreiber, W., Fassbender, K. C., & Holsboer, F. (1992) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/bf02190343 · Cited by 145 · see citing works
Self-citationHinze‐Selch, D. (2000) · Neuropsychopharmacology · doi:10.1016/s0893-133x(00)00089-0 · Cited by 141 · see citing works
TNF in the Inflammatory Response
M�nnel, D., & Echtenacher, B. (1999) · KARGER eBooks · doi:10.1159/000058757 · Cited by 121 · see citing works
Kutukculer, N., Caglayan, S., & Aydogdu, F. (1998) · Clinical Rheumatology · doi:10.1007/bf01451007 · Cited by 121 · see citing works
Influence of endotoxin on nocturnal sleep in humans
Pollmacher, T., Schreiber, W., Gudewill, S., Vedder, H., Fassbender, K., Wiedemann, K., Trachsel, L., Galanos, C., & Holsboer, F. (1993) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1993.264.6.r1077 · Cited by 119 · see citing works
Self-citationHumoral regulation of physiological sleep: cytokines and GHRH
Krueger, Obál, Jr., & Fang (1999) · Journal of Sleep Research · doi:10.1046/j.1365-2869.1999.00009.x · Cited by 112 · see citing works
Mediators of Inflammation and Their Interaction with Sleep
Mullington, J. M., Hinze‐Selch, D., & Pollmächer, T. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb05825.x · Cited by 107 · see citing works
Self-citationPollmächer, T., Korth, C., Mullington, J. M., et al. (1996) · Blood · doi:10.1182/blood.v87.3.900.bloodjournal873900 · Cited by 85 · see citing works
Self-citationKrueger, J. M., & Majde, J. A. (2009) · International Archives of Allergy and Immunology · doi:10.1159/000236827 · Cited by 64 · see citing works
Experimental Immunomodulation, Sleep, and Sleepiness in Humans
Pollmächer, T., Schuld, A., Kraus, T., Haack, M., Hinze‐Selch, D., & Mullington, J. M. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb05413.x · Cited by 61 · see citing works
Self-citationClow, A. (2002) · International review of neurobiology · doi:10.1016/s0074-7742(02)52012-2 · Cited by 48 · see citing works
Influence of host defense activation on sleep in humans
Pollmächer, T., Mullington, J. M., Korth, C., & Hinze‐Selch, D. (1995) · Advances in Neuroimmunology · doi:10.1016/0960-5428(95)00006-n · Cited by 48 · see citing works
Self-citationThe Effects of Fever on Sleep and Dream Patterns
Karacan, I., Wolff, S. M., Williams, R. L., Hursch, C. J., & Webb, W. B. (1968) · Psychosomatics · doi:10.1016/s0033-3182(68)71807-7 · Cited by 48 · see citing works
Haack, M., Reichenberg, A., Kraus, T., Schuld, A., Yirmiya, R., & Pollmächer, T. (2000) · Cytokine · doi:10.1006/cyto.1999.0665 · Cited by 47 · see citing works
Self-citationEffects of Sleep on Endotoxin-Induced Host Responses in Healthy Men
Haack, M., Schuld, A., Kraus, T., & Pollmächer, T. (2001) · Psychosomatic Medicine · doi:10.1097/00006842-200107000-00008 · Cited by 44 · see citing works
Self-citationCsako, G., McGriff, N. J., Rotman-Pikielny, P., Sarlis, N. J., & Pucino, F. (2001) · Annals of Pharmacotherapy · doi:10.1345/aph.1a031 · Cited by 40 · see citing works
Effects of granulocyte colony-stimulating factor on night sleep in humans
Schuld, A., Mullington, J., Hermann, D., Hinze-Selch, D., Fenzel, T., Holsboer, F., & Pollmächer, T. (1999) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1999.276.4.r1149 · Cited by 30 · see citing works
Self-citationPollmächer, T., Korth, C., Schreiber, W., et al. (1996) · Cytokine · doi:10.1006/cyto.1996.0106 · Cited by 21 · see citing works
Self-citationMangge, H., Gallist, S., & Schauenstein, K. (1999) · Journal of Interferon & Cytokine Research · doi:10.1089/107999099313217 · Cited by 21 · see citing works
Pollmächer, T., Schuld, A., Kraus, T., Haack, M., Hinze‐Selch, D., & Mullington, J. M. (2000) · Somnologie - Schlafforschung und Schlafmedizin · doi:10.1046/j.1439-054x.2000.12700.x · Cited by 5 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
The role of inflammation in CNS injury and disease
Lucas, S., Rothwell, N. J., & Gibson, R. M. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706400 · Cited by 1,272 · see citing works
Cytokines and major depression
Schiepers, O. J. G., Wichers, M. C., & Maes, M. (2005) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2004.11.003 · Cited by 1,235 · see citing works
Inflammatory mediators in the elderly
Krabbe, K. S., Pedersen, M., & Bruunsgaard, H. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2004.01.009 · Cited by 928 · see citing works
Godbout, J. P., Chen, J., Abraham, J., Richwine, A. F., Berg, B. M., Kelley, K. W., & Johnson, R. W. (2005) · The FASEB Journal · doi:10.1096/fj.05-3776fje · Cited by 813 · see citing works
Müller, N., Schwarz, M. J., Dehning, S., Douhe, A., Cerovecki, A., Goldstein-Müller, B., Spellmann, I., Hetzel, G., Maino, K., Kleindienst, N., et al. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001805 · Cited by 794 · see citing works
Evidence for a cytokine model of cognitive function
McAfoose, J., & Baune, B. T. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.10.005 · Cited by 760 · see citing works
Bercik, P., Verdu, E. F., Foster, J. A., Macri, J., Potter, M., Huang, X., Malinowski, P., Jackson, W., Blennerhassett, P., Neufeld, K. A., et al. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.06.063 · Cited by 674 · see citing works
Dinan, T. G., Quigley, E. M. M., Ahmed, S. M. M., Scully, P., O’Brien, S., O’Mahony, L., O’Mahony, S., Shanahan, F., & Keeling, P. W. N. (2006) · Gastroenterology · doi:10.1053/j.gastro.2005.11.033 · Cited by 636 · see citing works
Haack, M., Sanchez, E., & Mullington, J. M. (2007) · Sleep · doi:10.1093/sleep/30.9.1145 · Cited by 615 · see citing works
Self-citationCytokines as mediators of depression: what can we learn from animal studies?
Dunn, A. J., Swiergiel, A. H., & Beaurepaire, R. D. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.023 · Cited by 459 · see citing works
The risk factors for postpartum depression: A population-based study: S<scp>ilverman et al.</scp>
Silverman, M. E., Reichenberg, A., Savitz, D. A., Cnattingius, S., Lichtenstein, P., Hultman, C. M., Larsson, H., & Sandin, S. (2017) · Depression and Anxiety · doi:10.1002/da.22597 · Cited by 425 · see citing works
Self-citationWolkowitz, O. M., Mellon, S. H., Epel, E. S., Lin, J., Dhabhar, F. S., Su, Y., Reus, V. I., Rosser, R., Burke, H. M., Kupferman, E., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017837 · Cited by 421 · see citing works
Khairova, R. A., Machado-Vieira, R., Du, J., & Manji, H. K. (2009) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709009924 · Cited by 350 · see citing works
Neuroinflammation: Implications for the Pathogenesis and Molecular Diagnosis of Alzheimer's Disease
Rojo, L. E., Fernández, J. A., Maccioni, A. A., Jimenez, J. M., & Maccioni, R. B. (2008) · Archives of Medical Research · doi:10.1016/j.arcmed.2007.10.001 · Cited by 351 · see citing works
Godbout, J. P., Moreau, M., Lestage, J., Chen, J., Sparkman, N. L., Connor, J. O., Castanon, N., Kelley, K. W., Dantzer, R., & Johnson, R. W. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301649 · Cited by 299 · see citing works
Links between the innate immune system and sleep
Majde, J. A., & Krueger, J. M. (2005) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2005.08.005 · Cited by 277 · see citing works
Cytokines and acute phase response in delirium
de Rooij, S. E., van Munster, B. C., Korevaar, J. C., & Levi, M. (2007) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2006.11.013 · Cited by 261 · see citing works
Jeon, S. W., & Kim, Y. K. (2016) · World Journal of Psychiatry · doi:10.5498/wjp.v6.i3.283 · Cited by 247 · see citing works
Dose-dependent effects of endotoxin on neurobehavioral functions in humans
Grigoleit, J.-S., Kullmann, J. S., Wolf, O. T., Hammes, F., Wegner, A., Jablonowski, S., Engler, H., Gizewski, E., Oberbeck, R., & Schedlowski, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028330 · Cited by 241 · see citing works
A psychoneuroimmunological review on cytokines involved in antidepressant treatment response
Janssen, D. G. A., Caniato, R. N., Verster, J. C., & Baune, B. T. (2010) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.1103 · Cited by 240 · see citing works
Age and neuroinflammation: a lifetime of psychoneuroimmune consequences
Godbout, J. P., & Johnson, R. W. (2009) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2009.02.007 · Cited by 224 · see citing works
Overweight and Obesity Affect Treatment Response in Major Depression
Kloiber, S., Ising, M., Reppermund, S., Horstmann, S., Dose, T., Majer, M., Zihl, J., Pfister, H., Unschuld, P. G., Holsboer, F., et al. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.10.001 · Cited by 208 · see citing works
Schedlowski, M., Engler, H., & Grigoleit, J.-S. (2014) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2013.09.015 · Cited by 195 · see citing works
Low-dose endotoxemia and human neuropsychological functions
Krabbe, K. S., Reichenberg, A., Yirmiya, R., Smed, A., Pedersen, B. K., & Bruunsgaard, H. (2005) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2005.04.010 · Cited by 189 · see citing works
Self-citationInflammatory cytokine-associated depression
Lotrich, F. E. (2015) · Brain Research · doi:10.1016/j.brainres.2014.06.032 · Cited by 183 · see citing works
Bermejo, P., Martín-Aragón, S., Benedí, J., Susín, C., Felici, E., Gil, P., Ribera, J. M., & Villar, Á. M. (2008) · Immunology Letters · doi:10.1016/j.imlet.2008.02.002 · Cited by 178 · see citing works
The role of IL-12 and TGF-β1 in the pathophysiology of major depressive disorder
Lee, K.-M., & Kim, Y.-K. (2006) · International Immunopharmacology · doi:10.1016/j.intimp.2006.03.015 · Cited by 150 · see citing works
Neural-immune interactions in the regulation of sleep
Opp, M. R. (2003) · Frontiers in Bioscience · doi:10.2741/1061 · Cited by 92 · see citing works
Endotoxemia-induced inflammation and the effect on the human brain
van den Boogaard, M., Ramakers, B. P., van Alfen, N., van der Werf, S. P., Fick, W. F., Hoedemaekers, C. W., Verbeek, M. M., Schoonhoven, L., van der Hoeven, J. G., & Pickkers, P. (2010) · Critical Care · doi:10.1186/cc9001 · Cited by 84 · see citing works
Peripheral Chemo-Cytokine Profiles in Alzheimers and Parkinsons Diseases
Reale, M., Greig, N., & Kamal, M. (2009) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/138955709789055199 · Cited by 82 · see citing works
Diurnal and sleep–wake dependent variations of soluble TNF- and IL-2 receptors in healthy volunteers
Haack, M., Pollmächer, T., & Mullington, J. M. (2004) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2003.12.009 · Cited by 62 · see citing works
Self-citation
- Authors
- Pollmächer, T., Haack, M., Schuld, A., Reichenberg, A., & Yirmiya, R.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Pollmächer, Thomas
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 16
- Issue
- 5
- Pages
- 525-532
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W2007421151
- Cited by
- 202
- References
- 36
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 10 · 2017: 7 · 2016: 7 · 2015: 9 · 2014: 11 · 2013: 4 · 2012: 8
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- sickness behavior, depression, mood disorders, endotoxemia, NREM sleep, mood, memory
- MeSH terms
- Brain, Humans, Inflammation, Sleep, Cytokines, Mood Disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
