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Elements of the immune system: cytokines and co


Elements of the immune system: cytokines and co

1. Cytokines

Cytokines are proteins that are released by body cells in response to an activating stimulus. They bind to specific receptors and thus have a variety of effects. Over 50 cytokines are currently known.

1.1. Areas of action of cytokines

Cytokines have various effects:

  • Activation of the immune system in inflammatory processes
  • Regulation of the blood-brain barrier
  • Regulation of the HPA axis hormones
  • Excitatory and inhibitory effects on neurotransmitter systems
    • Dopamine
    • Serotonin
    • Noradrenaline
    • Acetylcholine

1.2. Types of cytokines

Cytokines differ in

1.2.1. Hematopoietins

  • Interleukins (IL, also known as lymphokines) are cytokines released by lymphocytes
    • IL-2
    • IL-3
    • IL-4
    • IL-5
    • IL-6
      (Former names: Interferon-β2 (IFNB2), B-cell stimulating factor, B-cell differentiation factor, liver cell stimulating factor)
      Release increased approx. 100-fold in response to heavy and prolonged muscle strain (6 hours). Maximum release at the end of muscle strain, followed by a rapid decline. Release partly from muscle cells themselves. Prolonged training causes a reduction in IL-6 release during exercise. IL-6 probably regulates immunological and metabolic responses to exercise via the liver, adipose tissue, the HPA axis and leukocytes. 1
      • Receptors:
      • IL-6R, only on liver cells and leukocytes
      • SIL-6R, soluble IL-6 receptor. Via this binding to binds to the glycoprotein gp130 in cell membranes of many cell types.
    • IL-7
    • IL-9
    • IL-11
    • IL-12
    • IL-13
    • IL-15
    • Erythropoietin (EPO)
    • Thrombopoietin (TPO)
    • Leukemia inhibitory factor (LIF)
    • G-CSF
    • GM-CSF

1.2.2. Tumor necrosis factor (TNF)

  • TNF
    • Effects:
      • Hypothalamus:
        • Increases CRH
        • Inhibits appetite
        • Regulates fever
      • Liver:
        • Forms acute phase proteins
          • C-reactive protein (CRP).
      • Macrophages:
        • Stimulates phagocytosis.
      • Neutrophil granulocytes
        • Promoting migration.
      • In general:
        • Increases insulin resistance
        • Increases cyclooxygenase-2 activity
        • Local increase causes inflammation
          • Heat
          • Redness
          • Swelling
          • Pain
        • Extreme increase causes shock
    • Bupropion reduces the TNF-alpha level.2

1.2.3. Interferons

Interferons are antiviral proteins that are produced by cells in response to a viral infection. They inhibit the replication of viruses.

  • Alpha interferon (IFN-α) (formerly: type I)
  • Beta-interferon (IFN-β)
  • Gamma interferon (IFN-γ)
    • Activates macrophages by improving the fusion of phagosomes with lysosomes and promoting the production of bactericidal nitric oxide and reactive oxygen radicals
    • Induces antimicrobial peptides
    • Induces 1α-hydroxylase in macrophages
    • Converts 25(OH) vitamin D3 into 1,25(OH)2 vitamin D3 without product inhibition of 1α-hydroxylase
  • Tau interferon

1.2.4. Chemokines

Chemokines are released by various cells in response to bacteria or viruses. They can chemically direct leukocytes (chemoattractants). There are 4 groups: CC, CXC. C3 and C. A comprehensive list can be found on Wikipedia.3. Many chemokines have several names. IL-8 is another name for CXC-8.

1.3. Differentiation according to TH-1 and TH-2 affiliation

1.3.1. TH-1 cytokines

TH-1 cytokines are pro-inflammatory cytokines that are primarily promoted by stress hormones of the first two stages of the HPA axis (CRH and ACTH) and are inhibited by cortisol.

  • TNF45
  • TNF-β,5
  • IFN-α65
  • IFN-γ45
  • IL-5
  • IL-45
  • IL-24
  • IL-645
  • IL-845
  • IL-126
  • IL-187
  • Macrophage inhibitory protein-15

Disease patterns with a shift of the immune system towards TH-1 are, for example

  • Rheumatoid arthritis6
  • Multiple sclerosis6
  • Type 1 diabetes mellitus6
  • Autoimmune thyroid disease6
  • Collagen- and adjuvant-induced arthritis6
  • Experimental allergic/autoimmune encephalomyelitis6

1.3.2. TH-2 cytokines

TH-2 cytokines are anti-inflammatory cytokines that are primarily promoted by stress hormones of the third stage of the HPA axis (cortisol).

  • IL-1ra (receptor antagonist)45
  • IL-44
  • IL-54
  • IL-96
  • IL-104
  • IL-117
  • IL-136
  • IL-25
  • Soluble IL-1 Receptor5
  • TNF-α binding protein5
  • IL-1 binding protein5

In addition, TH-2 dominance of the immune system is associated with increased histamine6 and IgE production.8

1.3.3. TH-17

  • IL-17

1.3.4. TH-reg

2. Other inflammatory biomarkers

2.1. Acute phase proteins

2.1.1. C-reactive protein (CRP)

CRP is an acute-phase protein that becomes measurable 12 to 24 hours after the onset of an infection. It activates the complement immune system. CRP is an important indicator for the activation of the immune system.

2.2. Microglia

Microglia are certain glial cells with the function of tissue macrophages. Unlike most cells, they do not develop from the bone marrow, but from yolk sac cells.

There are two types of macrophage activation: M1 and M2.
The activation of microglial cells is triggered by the M1 phenotype, which is associated with an increase in IL-1β and TNF-α. In contrast, the M2 phenotype is associated with the release of anti-inflammatory cytokines.9

3. Cytokines in the brain: migration and development

3.1. Migration of cytokines into the brain

Peripheral cytokines can enter the brain or be produced there via various routes:10

  • Direct or carrier-mediated passage of the blood-brain barrier
  • Activation of endothelial cells and perivascular macrophages in the blood vessels of the brain
  • Local activation of peripheral nerves (e.g. vagus), which then transmit cytokine signals to relevant brain regions, e.g. to the solitary nucleus or hypothalamus
  • Peripherally recruited activated immune cells (e.g. monocytes, macrophages, T cells) into the brain

Cytokines such as IFN-a, IFN-c, IL-2, IL-10, IL-1, IL-6 and TNF-a can cross the blood-brain barrier, bind to receptors of vagal sensory nerves and stimulate the HPA axis.11

Disorders of the blood-brain barrier are found in 20 to 30 % of psychiatric patients. This is usually accompanied by activation of the astrocytes. It is assumed that the disruption of the blood-brain barrier is the result of mild chronic inflammation.12

3.2. Development of cytokines in the brain

Cytokines are produced in the brain by10

  • Microglia (mainly)
  • Astrocytes
  • Nerve cells
  • Oligodendrocytes

Endothelial cells and perivascular macrophages are stimulated by cytokines to express the prostaglandin-producing enzymes cyclooxygenase-2 (COX-2) and prostaglandin E synthase (PGES).10

4. Measurement of cytokines: CSF / serum

Pro-inflammatory cytokines are detectable in the brain and in the blood. The measurement of cytokines in the blood is primarily related to their immunological effects. Cytokines that are present in the blood also reach the brain. Conversely, this is not always the case. Since the neuropsychological effects, i.e. the change in behavior, are mediated in the brain and cytokines that are present in the brain are not detectable to the same extent in the blood, measuring cytokines in the blood makes little sense in terms of determining neuropsychological influences.13


  • Peripherally administered IFN-α reduces the L-tryptophan level in the blood, but not the L-tryptophan level in the cerebrospinal fluid.14
  • A single administration of endotoxin in mice immediately increases TNF-α levels. While peripheral TNF-α decreased in serum after 9 h and in the liver after 1 week, it remained elevated in the brain for 10 months.15
  • Cytokines are partly transported through the blood-brain barrier, but are also synthesized in astrocytes and microglia directly in the brain.12
  • IL-2 in the blood does not represent the symptoms mediated by IL-2 in the brain. Thus, only CSF IL-2, but not blood IL-2, has a prognostic value in relation to schizophrenia.12
  • The effects of IL-1-beta on IL-6 changes in the blood differ from the effects on IL-6 in the cerebrospinal fluid.16
  • Quinolinic acid, which mediates considerable behavioral deficits, showed no correlation between blood values and cerebrospinal fluid values in a study despite significantly increased values in the brain.17

This also applies to neurotransmitters and hormones.

The DHEA values in the brain are on average 6.5 times the blood value, but the DHEA values in the cerebrospinal fluid are only 1/20 of the blood values.18

While acute and severe neuroinflammation of the brain is not easy to measure and diagnose, chronic or low-threshold neuroinflammation is even more difficult to detect and assess. Measurements of cerebrospinal fluid are characteristic of acute meningoencephalitis, more difficult in acute encephalitis without meningitis and very difficult in low-threshold neuroinflammation and can only be evaluated with a high level of expertise. Measurements should always include pairs of cerebrospinal fluid and serum samples taken simultaneously in order to recognize the dynamics of the exchange between the blood and cerebrospinal fluid. All immunoglobulin subclasses should always be examined and the respective quotients compared with Q-albumin. The final classification is based on the complete set of all parameters of serum, cerebrospinal fluid and cells in order to detect outliers and errors in the data set more quickly. Even this approach cannot completely rule out acute encephalitis, as CSF obtained lumbally (= from the back) may have little significance with regard to the cerebral cortex or CSF from subarachnoid spaces of the brain.19

  1. Fischer (2006): Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev. 2006;12:6-33.

  2. Wilkes (2006): Bupropion. Drugs Today (Barc). 2006 Oct;42(10):671-81.


  4. Assaf, Al-Abbassi, Al-Binni (2017): Academic stress-induced changes in Th1- and Th2-cytokine response. Saudi Pharm J. 2017 Dec;25(8):1237-1247. doi: 10.1016/j.jsps.2017.09.009.

  5. Gruys E1, Toussaint MJ, Niewold TA, Koopmans (2005): Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B. 2005 Nov;6(11):1045-56.

  6. Elenkov (2004): Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004 Jun;1024:138-46.

  7. Heizmann, Koeller, Muhr, Oertli, Schinkel (2008): Th1- and Th2-type cytokines in plasma after major trauma. J Trauma. 2008 Dec;65(6):1374-8. doi: 10.1097/TA.0b013e31818b257d.

  8. Humbert, Menz, Ying, Corrigan, Robinson, Durham, Kay (1999): The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences, Immunology Today, Volume 20, Issue 11, 1999, Pages 528-533, ISSN 0167-5699,

  9. Réus, Fries, Stertz, Badawy, Passos, Barichello, Kapczinski, Quevedo (2015): The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders, Neuroscience, Volume 300, 2015, Pages 141-154, ISSN 0306-4522,

  10. Felger, Miller (2012): Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol. 2012 Aug;33(3):315-27. doi: 10.1016/j.yfrne.2012.09.003.

  11. Verlaet, Noriega, Hermans, Savelkoul (2014): Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry. 2014 Jul;23(7):519-29. doi: 10.1007/s00787-014-0522-2.

  12. Müller: Psychoneuroimmunologische Grundlagen psychischer Erkrankungen, in: Möller, Laux, Kapfhammer (Hrsg.) (2017): Psychiatrie, Psychosomatik, Psychotherapie, Band 1, 5. Auflage, Kapitel 11, S. 291 – 310

  13. Bieger: ME/CFS – die unbekannte Krankheit,

  14. Raison, Dantzer, Kelley, Lawson, Woolwine, Vogt, Spivey, Saito, Miller (2010): CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: relationship to CNS immune responses and depression. Molecular Psychiatry volume 15, pages 393–403, 2010

  15. Qin, Wu, Block, Liu, Breese, Hong, Knapp, Crews (2007): Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55: 453-462. doi:10.1002/glia.20467

  16. Reyes, Coe (1996): Interleukin-1 beta differentially affects interleukin-6 and soluble interleukin-6 receptor in the blood and central nervous system of the monkey. J Neuroimmunol. 1996 May;66(1-2):135-41.

  17. Heyes, Saito, Lackner, Wiley, Achim, Markey (1998): Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. The FASEB Journal 1998 12:10, 881-896

  18. Maninger, Wolkowitz, Reus, Epel, Mellon (2009): Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Frontiers in Neuroendocrinology, Volume 30, Issue 1, 2009, Pages 65-91, ISSN 0091-3022,

  19. Bechter (2012): Diagnosis of infectious or inflammatory psychosyndromes. Open Neurol J. 2012;6:113-8. doi: 10.2174/1874205X01206010113.

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