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Effect of individual cytokines and inflammatory markers

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Effect of individual cytokines and inflammatory markers

This article presents individual cytokines and inflammatory markers as well as their neurophysiological and behavioral effects.
Proinflammatory cytokines have a considerable influence on the dopamine, noradrenaline and serotonin balance, cause an activation of the HPA axis and an increase in acute-phase proteins. They therefore have neurophysiological effects similar to those of ADHD.
Some cytokines, such as IL-6 and IL-10, appear to be directly related to ADHD. IFN-α can cause dopamine deficiency in the striatum, as occurs in ADHD. However, the associated symptoms can be reduced by L-dopa, whereas L-dopa is not known to improve the symptoms of ADHD. At the same time, the dopaminergically mediated symptoms of IFN-α administration (here: fatigue) respond only weakly to treatment with the stimulants that are effective in ADHD, which act as reuptake inhibitors of dopamine and noradrenaline and increase the extracellular dopamine level through DAT efflux.

1. Cytokines

1.1. Interferons

1.1.1. Interferon alpha (IFN-α)

IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, while IFN-γ binds to the interferon type 2 receptor (IFNGR).1

1.1.1.1. Neurophysiological effects of IFN-α

The studies on the effects of IFN-α on dopamine levels show inconsistent results. This is partly due to the fact that rodents were treated with human IFN-α, although rodents do not have IFN type 1 receptors, so that the statements are only of limited significance.2 Inconsistent results for IFN-α exist not only for dopamine, but also in relation to noradrenaline and serotonin.1

1.1.1.1.1. Influence of IFN-α on dopamine, serotonin and noradrenaline
  • IFN-α reduces dopaminergic activation of the striatum, which is associated with anhedonia, fatigue and depression 3 45
    • This also correlates with changes in motivation.6
  • IFN-α reduces dopamine and tetrahydrobiopterin (BH4) levels in the amygdala and raphe nuclei (IFN-α given to muscles).7 Cardiotrophin-1 (CT-1) and IN-6 also reduce BH4 levels8
    • It is unclear whether this is mediated by nitrogen oxide. This was partly affirmed,7 partly denied.9
  • IFN-α, given peripherally, increased2
    • IFN-α in the brain through microglia and astrocytes
      IFN-α occurs in lower quantities than IL-6 and MCP-1, IFN-α in the brain in turn increases
    • IL-6 in the brain
    • IL-1 in the brain through microglia
    • TNF-α in the brain
    • MCP-1 (monocyte chemoattractant protein-1) in the brain
    • Oxidative stress (superoxidants) in the brain due to microglia
  • Hepatitis C-infected patients received IFN-α and an L-dopa (F-dopa) measurable by radioactivity. IFN-α significantly increased F-dopa uptake and decreased F-dopa turnover in the caudate nucleus, putamen and those areas of the ventral striatum that were less activated by IFN-α. The changes in F-dopa uptake and turnover correlated with depression and fatigue3
    • Parkinson’s disease, on the other hand, is observed:
      • Reduced F-dopa uptake and increased turnover of F-dopa10
      • Reduced F-dopa uptake in the putamen and increased uptake in the PFC11
      • Reduced activity and dopamine storage in the striatum12
  • Noradrenaline and dopamine levels and tyrosine hydroxylase in rats were increased by IFN-α administered for 7 days13
    • Significantly increased in
      • PFC
      • Hypothalamus
      • Medulla oblongata
    • Unchanged in
      • Thalamus
      • Hippocampus
  • An injection of IFN-α into the brain in rats within 2 hours14
    • Serotonin reduced
      • Significant dose-dependent reduction in PFC
      • Reduction in the middle brain
      • Reduction in the striatum
    • 5-Hydroxyindoleacetic acid (5-HIAA) reduces
      • Reduction in the middle brain
      • Reduction in the striatum
    • Noradrenaline reduced
      • Significant dose-dependent reduction in PFC
  • IFN-α reduces tryptophan levels (albeit to a lesser extent than IFN-γ), which suggests an inhibitory effect on serotonin.1
  • IFN-α injected into the abdomen over 14 days in rats9
    • Dopamine reduced
      • Reduced after 1 day in the cortex
      • Reversible after the end of IFN-α administration
    • Noradrenaline reduced
      • Reduced in most brain regions after 4 days
      • Reversible after the end of IFN-α administration
    • Increased serotonin
      • After 14 days at 20,000 U/kg increased in
        • PFC
        • Hippocampus
      • After 14 days at 200,000 U/kg increased in
        • PFC
        • Hippocampus
        • Amygdala
        • Thalamus
        • Hypothalamus
      • After 14 days at 2,000,000 U/kg increased in
        • Thalamus
        • Hypothalamus
      • No change in serotonin transporter mRNA levels
  • IFN-α injected once into the peritoneum at 1,500,000 U/kg, 3,000,000 U/KG or 6,000,000 U/kg did not significantly alter monoamines, monoamine metabolites or monoamine turnover in rats15
  • IFN-α of 1,500,000 U/kg injected into the peritoneum for 5 consecutive days in rats15
    • Dopamine levels significantly reduced
    • 3,4-Dihydroxyphenylacetic acid levels significantly reduced
    • Dopamine degradation induced by α-methyl-p-tyrosine is significantly suppressed.
  • IFN-α over 4 weeks in monkeys caused a reduced increase in dopamine in the striatum due to amphetamines. This correlated with anhedonia.
    • This IFN-α-induced striatal dopamine reduction was completely reversed by L-dopa,16 suggesting that IFN-α impairs the synthesis of dopamine.
    • The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which increases when unpackaged dopamine is metabolized via monoamine oxidase, remained unchanged, suggesting that IFN-α does not affect dopamine levels via monoamine oxidase.16
    • Furthermore, the binding of the D2 dopamine receptor was reduced, but not that of the dopamine transporter.17

MPH shows no effect on fatigue in cancer.181920 Amantadine also showed only a minor effect on fatigue in multiple sclerosis, as did modafinil. A very large and comprehensive meta-study of 113 studies with n = 11,525 subjects found no better effect on fatigue in cancer for either amphetamines or medication than for exercise and psychotherapy. The accompanying material of the meta-study provides a very good overview.212223

1.1.1.1.2. Influence on glutamate through IFN-α

IFN-α increases glutamate in the basal ganglia and dorsal ACC (dACC) in non-depressed individuals.24

1.1.1.1.3. Influence of IFN-α on the HPA axis

IFN activates the HPA axis in humans, but hardly at all in rodents.1 HPA axis changes were observed:

  • Cortisol
    • The changes in cortisol levels correlated with depression25
    • Flattened daily cortisol curve25
      • This correlated significantly with
        • Reduced activity
        • Reduced motivation
        • Physical exhaustion (fatigue)
        • Mental exhaustion
        • But not with general fatigue
      • The morning cortisol increase did not correlate with behavioral changes
    • Elevated evening cortisol level25
      • An increase in evening cortisol minimums correlated significantly with increased depression scores on the MADRS and increased fatigue scores on the MFI and all its subscales (general fatigue, physical fatigue, decreased activity, decreased motivation, mental fatigue)
      • Elevated evening cortisol levels correlated with stress experienced that day26
  • ACTH
    • Flattened daily ACTH curve25
      • ACTH changes did not correlate with behavioral changes
    • Elevated evening ACTH value25
      • ACTH changes did not correlate with behavioral changes
  • Stimulation of the HPA axis27
    • A single administration of 5 million IU IFN-α activates the HPA axis
    • After a daily administration of 5 million IU IFN-α over 3 weeks, no increased ACTH and cortisol blood levels were detected. However, supramaximal doses of CRH triggered significantly increased ACTH and cortisol levels.
    • In the laboratory, IFN-α stimulates CRF production in the hypothalamus and corticoid secretion in the adrenal cortex (in rats), but not ACTH secretion by the pituitary gland.
1.1.1.1.4. Further effects of IFN-α
  • IFN-α increased glucose metabolism in the basal ganglia and cerebellum, while decreasing it in the dorsal PFC. It caused exhaustion, alexithymia (lack of emotion) and fatigue.28
  • This increased glucose metabolism in the basal ganglia nuclei is similar to that of Parkinson’s patients, where it reflects increased oscillatory burst activity due to loss of inhibitory nigral dopamine input.2
  • IFN-α potentiates the dopaminergic effect of D-amphetamine. The mu-opioid receptor antagonist naloxone suppressed this increase in effect, which is why it is possibly mediated via opioid receptors.292
  • IFN-α reduces the perception of pain in rats. This effect can be prevented by mu-opioid receptor antagonists (e.g. naloxone), but not by delta or kappa-opioid receptor antagonists.30
1.1.1.2. Behavioral effects of IFN-α
1.1.1.2.1. Fever

IFN-α increases fever in humans, but hardly in rodents.1

1.1.1.2.2. Cognitive impairments

Cognitive impairments caused by IFN-α correlate significantly with a prolonged latency of P300.31

1.1.1.2.3. Depression, anhedonia, fatigue
  • Anhedonia, fatigue and depression due to IFN-α
    • Due to reduced dopaminergic activation of the striatum3245
    • This also correlates with a change in motivation.6
    • Depression and fatigue correlated with increased F-dopa uptake and decreased L-dopa turnover on long-term IFN-α administration.33
    • Depressive behavior (huddling, huddling) correlated with reduced homovanillic acid in the cerebrospinal fluid, a metabolic product of dopamine, indicating reduced dopamine turnover.2
    • Fatigue correlated with reduced homovanillic acid in the cerebrospinal fluid, a metabolic product of dopamine, which indicates a reduced dopamine turnover.34
    • Anhedonia16
      • Correlated with a reduced increase of dopamine in the striatum by amphetamines after IFN-α administration for 4 weeks in 8 monkeys.
      • This IFN-α-induced striatal dopamine reduction was completely reversed by L-dopa, indicating that IFN-α impairs the synthesis of dopamine.
1.1.1.2.4. Fear

Rhesus monkeys treated permanently with IFN-α showed2 in 3 out of 8 animals35

  • Increasing anxiety behavior
  • A decrease in psychomotor activity
  • An increase in depressive-like huddling (huddling)
  • Signs of depression were only present in the 3 animals that
    • Had significantly reduced dopamine metabolites in the cerebrospinal fluid:
      • Homovanillic acid (HVA)
      • 3,4-Dihydroxyphenylacetic acid (DOPAC)
    • Which correlated with reduced motor activity
  • Increased values of
    • ACTH
    • Cortisol
    • IL-6
  • Anhedonia36
1.1.1.2.5. Sleep impaired
  • IFN-α impairs sleep372
    • Increased nocturnal awakening
      • Correlates with elevated evening cortisol levels
    • Impaired REM sleep
      • This is mediated via the dopamine level38
      • Correlates with increased fatigue
    • Increased stage 2 sleep (medium non-REM sleep)
    • Reduced deep sleep
      • Correlates with increased fatigue
    • Poorer sleep efficiency
      • Correlates with slower motor speed
    • No increased daytime tiredness
      • Reduced frequency of power naps
1.1.1.2.6. Reduced motor activity

IFN-α decreased motor activity in rats (7-day administration).13 The decreased motor activity correlated with decreased cerebrospinal fluid homovanillic acid, a metabolite of dopamine, indicating decreased dopamine turnover.34

1.1.1.2.7. No effects of IFN-α
  • Response time6
  • Executive functions6
  • Accuracy in the concentration test6
1.1.1.2.1. IFN-α and depression

Pretreatment with an antidepressant (here: paroxetine) prevented IFN-α-induced depression, anxiety, cognitive impairment and pain better than anorexia and fatigue.3940
In a double-blind study, paroxetine showed no effect on ADHD.41 Pegylated IFN-α with a reduced half-life leads to fewer depressive symptoms than non-pegylated IFN-α.42
The triggering of depressive symptoms (but not the other symptoms) by IFN-α could be mediated by the reduction of tryptophan (TRP) due to its conversion to kynurenine (KYN) by the enzyme indoleamine-2,3-dioxygenase.43
As a drug against hepatitis C or malignant melanoma, IFN-α 2 b triggers severe depression in 40 to 50 % of those affected in a dose-dependent manner and fatigue, loss of energy and motor slowdown in up to 80 %.44 Plasma levels of IFN-α correlate highly with depression characteristics according to the MADRS and fatigue values according to the MFI.25

Anorexia, fatigue and pain did not occur immediately, but only within 14 days of starting IFN-α treatment. Depressed mood, anxiety and cognitive impairment, on the other hand, only occurred later and mainly in patients who met the DSM-IV criteria for major depression.

IFN-α has two pathways of action45

  • Rapidly occurring consequence: neurovegetative syndrome
    • Psychomotor deceleration
    • Tiredness
    • Changes in the dopamine metabolism of the basal ganglia
    • Does not respond to antidepressants
  • Late-onset consequence: depressive syndrome
    • Depressive symptoms
    • Activation of neuroendocrine pathways
    • Altered serotonin metabolism
    • Responds to antidepressants

Different pathways for different depression subtypes?

We wonder whether the different depressive consequences of the neurovegetative system (dopaminergic) and the depressive syndrome (serotonergic) might also explain some differences between melancholic and atypical depression. While atypical depression tends to be associated with a flattened endocrine stress response and increased daytime sleepiness, melancholic depression is typically associated with an increased endocrine stress response without increased daytime sleepiness. If there is a link here, atypical depression, which is more strongly associated with daytime sleepiness, should respond better to dopaminergic treatment.

IFN-α-induced depression and “naturally” occurring depression show46

  • Identical symptom severity of
    • States of anxiety
    • Depressive mood
    • Impaired work activity
  • Deviating in IFN-α-induced depression
    • Stronger psychomotor deceleration
    • Higher weight loss
    • Feeling less guilty

Parameters that make depression more likely after antiviral treatment with interferon are:47

  • High baseline levels of IL-6
  • Female gender
  • Previous depression
  • Subliminal symptoms of depression
  • Low level of education

Antidepressants have the effect of reducing the production of pro-inflammatory cytokines (such as IFN-α) and increasing the production of anti-inflammatory cytokines.48

1.1.2. IFN-β

IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, while IFN-γ binds to the interferon type 2 receptor (IFNGR).1

1.1.3. IFN-γ

IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, while IFN-γ binds to the interferon type 2 receptor (IFNGR).1

IFN-γ and IL-12 inhibit the activity of TH-2 cells.49

IL-6, IL-10, IL-17, IFN-γ And TNF-α are little affected by alcohol consumption (to 1.2 per mille).50

Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte-LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the non-stressed state.
Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in pro-inflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.51

IFN-α reduces tryptophan5248 (more strongly than IFN-α), which suggests an inhibitory influence on serotonin.1

1.1.3.1. IFN-γ for ADHD

The only cerebrospinal fluid study to date found IFN-γ in 60% of children with ADHD.53

One study found no changes in serum levels of IL-2, IL-4, IL-17, TNF-α and IFN-γ in children with ADHD.54
Blood serum values are often inconclusive with regard to the neuropsychological effects of cytokines. See here: Measurement of cytokines

1.2. Interleukins

1.2.1. IL-1

1.2.1.1. IL-

IL-1α and IL-1β appear to have very similar effects. IL-1β is said to be more potent in activating the HPA axis.1
IL-1α and IL-1β both bind to the IL-1 type 1 receptor, which mediates their effect.
The IL-1 type 2 receptor only appears to bind IL-1 without mediating its own effects. It thus acts as a kind of IL-1 antagonist. IL-4 and dexamethasone increase the formation of IL-1 type 2 receptors.55
The IL-1 receptors in humans differ considerably from animal variants.1

Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte-LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the non-stressed state.
Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.51

IL-1, TNF-α and IL-6 trigger various reactions:56

1.2.1.1.1. Neurophysiological effect of IL-
1.2.1.1.1.1. Increased turnover of noradrenaline, dopamine, serotonin
  • IL-1 increases noradrenaline turnover in the hypothalamus (which activates the HPA axis) as well as ACTH and blood cortisol levels and tryptophan levels. The maximum occurred after 4 hours.57 In addition to noradrenaline in the hypothalamus, IL-1 also increases serotonin turnover in the entire brain1
    • The IL-1-mediated increase in noradrenaline turnover is lower in the brain regions innervated by the dorsal noradrenergic bundle57
      • PFC
      • Hippocampus
      • Cerebellum
    • The noradrenergic effect of IL-1 appears to be mediated by cyclooxygenase 2 (COX2). COX2 antagonists (diclofenac) prevent increased noradrenaline turnover induced by IL-1, but not COX-1 antagonists (indomethacin, ibuprofen) or lipoxygenase antagonists.58 However, indomethacin was able to prevent the increase in noradrenaline in response to intravenously administered IL-1, but not the increase in response to IL-1 administered intraperitoneally (into the peritoneum). Intravenously administered IL-1 also led to faster HPA axis activation than IL-1 administered into the peritoneum.
  • IL-1 causes an increase in the turnover (which leads to a reduction in the level) of59
    • Noradrenaline in the hypothalamus and hippocampus
    • Serotonin in the hippocampus and PFC
    • Dopamine in the PFC
  • IL-1 causes cortisol elevation in the blood, but this did not correlate significantly with the noradrenaline elevation
  • The sometimes increased dopamine consumption by IL-1 in mice did not resemble the usual pattern of increased dopamine turnover in the PFC relative to other brain areas during stress1
1.2.1.1.1.2. HPA axis activation
  • Activation of the HPA axis60 by IL-1 is primarily due to the increased noradrenaline level. IL-1β is thought to be more potent in terms of activating the HPA axis1
    • IL-1 increases the release of ACTH61
1.2.1.1.1.3. Acute phase proteins increased
  • Increase in acute phase proteins60
1.2.1.1.2. Behavioral changes
1.2.1.1.2.1. Fever
1.2.1.1.2.2. Sickness behavior
  • As well as TNF-α, unlike IL-2 single dose62
  • Reduced food intake60
  • Reduced water absorption
  • Trembling
  • Increased drowsiness
  • Reduced social interest.
1.2.1.1.2.3. Anxiety symptoms
  • As well as TNF-α, unlike IL-2 single dose62
1.2.1.1.2.4. Anorexia
  • As well as TNF-α, unlike IL-2 single dose62
1.2.1.1.2.5. Sleep
  • IL-1 induces sleep61
1.2.1.1.2.6. No influence of IL-1
  • No influence on reward processes / motivation (anhedonia)
    • As well as TNF-α, unlike IL-2 single dose62
1.2.1.1.2. Effects on IL-

Inhaled particulate matter was found in the brain tissue of mice and increased the level of IL-1α there.63

1.2.1.2. IL-
1.2.1.2.1. Neurophysiological effect of IL-
1.2.1.2.1.1. Influences on noradrenaline, dopamine, serotonin
  • An increase in tyrosine hydroxylase due to IL-1-beta indicates increased dopamine turnover in the hypothalamus. The change correlated with increased ACTH levels with unchanged prolactin levels.64
  • IL-1-β potentiated the mild stress-induced dopamine increase by mild stress in the PFC.65
  • IL-1-β increases the activity of the serotonin transporter, which leads to increased degradation of serotonin.6667
  • IL-1 causes an increase in the turnover (which leads to a reduction in the level) of59
    • Noradrenaline in the hypothalamus and hippocampus
    • Serotonin in the hippocampus and PFC
    • Dopamine in the PFC
  • IL-1 causes cortisol elevation in the blood, but this did not correlate significantly with the noradrenaline elevation
  • The effects of IL-1β in rats depend considerably on the type of application (injected into the brain = intracerebroventricular or into the peritoneum = intraperitoneal = peripheral)68
    • Noradrenaline
      • Decreases in limbic regions due to prolonged administration
    • Serotonin
      • Increased in limbic regions through prolonged administration
    • Dopamine
      • Increased in limbic regions through prolonged administration
    • Sensitivity to stress
      • Increased
    • Increase in blood cortisol
      • Through acute and prolonged administration of IL-
    • Reduction of IL-10
      • Through acute and prolonged administration of IL-
    • PGE2 release
      • Increased by IL-1β released into the brain
      • Reduced by peripheral IL-1β administration
1.2.1.2.1.2. Inhibition of neurogenesis
  • IL-1-β inhibits neurogenesis in the hippocampus69
    • Neurogenesis with the maturation of neuronal stem cells in the hippocampus is of central importance for cognitive function.707169 One of the modes of action of antidepressants is the suppression of mechanisms that impair neurogenesis.72
    • Cortisol also inhibits neurogenesis.73
1.2.1.2.1.3. Inhibition of long-term potentiation
  • IL-1β administration prevents long-term potentiation (LTP), which is essential for long-term memory. 74 LTP inhibition is prevented by administering the antioxidant vitamins E and C.
    • The inhibition of LTP correlates with:
      • IL-1β increase in the dentate gyrus
      • Decrease in KCl-stimulated glutamate release in synaptosomes from the dentate gyrus
        • LTP is associated with increased glutamate release
        • Decrease in KCl-stimulated glutamate release is prevented by administration of the antioxidant vitamins E and vitamin C
      • Increase in unstimulated glutamate release
      • Increased activity of stress-activated kinases
      • Increased activity of the c-Jun N-terminal kinase (JNK)
      • Increased activity of the p38 mitogen-activated protein kinase
    • An intracerebroventricular (= given into the brain) injection of IL-1β increased oxygen radicals in the hippocampus.
      • Is prevented by the administration of the antioxidant vitamins E and C
    • IL-1β and H²O² increase the activities of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase
      • Is prevented by the administration of the antioxidant vitamins E and C
1.2.1.2.1.3. HPA axis activation

IL-1 increases the release of ACTH.61

1.2.1.2.1.4. Striatum connectivity - vmPFC

High IL-6, IL-1β and IL-1-RA levels correlate with reduced connectivity between striatum and vmPFC.75

1.2.1.2.2. Behavioral change through IL-
1.2.1.2.2.1. Cognitive performance

The higher the IL-1β, IL-6, and IL-8 stress response to an emotionally stressful movie, the greater the stress-related impairment of cognitive control/performance in the Stroop test.76

Spatial memory is only impaired by long-term administration of IL-1β into the brain, not by short-term administration or peripheral administration into the peritoneum.68

Neonatal rats treated with endotoxin respond to repeated endotoxin treatment in adulthood:77

  • Increased gene expression for microglia cell markers in the hippocampus
  • A stronger increase in the gene expression of glial cell markers in the hippocampus
    • This increase remained elevated for 24 h longer
  • A faster increase in IL-1beta in the hippocampus and PFC
  • A prolonged increase in IL-1-beta in the PFC
  • Peripheral cytokines or basal corticosterone were unchanged
  • Impaired memory
    • This could be prevented by administering a caspase-1 inhibitor to the adult animals 1 hour before the learning event and the subsequent endotoxin administration.
      A caspase-1 inhibitor prevents the synthesis of IL-1beta
1.2.1.2.2.2. Anhedonia / reward motivation reduced

Peripheral administration of IL-1β reduced the effort shown for sugar rewards compared to freely available food. The preference for sugar over freely available food was not reduced. This suggests that IL-1β reduces the level of reward stimuli (anhedonia). This is similar to the effect of IFN-α.78

1.2.1.2.2.3. Stimulating sleep

IL-1 induces sleep.61

1.2.1.2.2.4. Movement activity

The behavioral effects of IL-1β in rats depend considerably on the type of application (injected into the brain = intracerebroventricular or into the peritoneum = intraperitoneal = peripheral).68

  • Movement activity:
    • Elevated (into the peritoneum)
    • Reduced (into the brain)
1.2.1.2.2.5. Anxiety

The behavioral effects of IL-1β in rats depend significantly on the type of administration (into the brain = intracerebroventricular or into the peritoneum = intraperitoneal = peripheral).68 Anxiety is increased even more after IL-1β administration into the brain than after IL-1β administration into the peritoneum.

1.2.1.2.3. Behavioral changes depending on application location and duration

The behavioral effects of IL-1β in rats depend considerably on the type of application (injected into the brain = intracerebroventricular or into the peritoneum = intraperitoneal = peripheral).68

  • Movement activity:
    • Elevated (into the peritoneum)
    • Reduced (into the brain)
  • Anxiety
    • Increased after administration into the peritoneum
    • More elevated when administered into the brain
  • Spatial memory
    • Only impaired by prolonged administration into the brain
  • Increase in blood cortisol
    • Through acute and prolonged administration of IL-
  • Reduction of IL-10
    • Through acute and prolonged administration of IL-
  • PGE2 release
    • Increased by IL-1β- released into the brain
    • Reduced by peripheral administration
  • Noradrenaline
    • Reduced in limbic regions through prolonged administration
  • Serotonin
    • Increased in limbic regions through prolonged administration
  • Dopamine
    • Increased in limbic regions through prolonged administration
  • Stress sensitivity
    • Increased
1.2.1.2.4. Effects on IL-
1.2.1.2.4.1. Stress increases IL-
  • Psychological stress (on TSST as well as on angry memory retrieval) leads to an increase in IL-1β, TNF-α and IL-6 in the sense of a stress response. The stress-induced increase in IL-1β, TNF-α and IL-6 correlates with negative emotions.79
  • A further study confirms this for IL-1-b and TNF-a and, to a lesser extent, for CRP.80
  • The higher the IL-1β, IL-6, and IL-8 stress response to an emotionally stressful movie, the greater the stress-related impairment of cognitive control/performance in the Stroop test.76
  • In women, stress caused by an interview led to an increase in81
    • Plasma cortisol
    • Noradrenaline
    • IL-
    • IL-10
    • TNF-a
    • Number and activity of natural killer cells
  • In women, stress caused by sleep deprivation led to an increase in82
    • IL-
    • TNF
    • Natural killer cells.
  • Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte-LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the non-stressed state.
    Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.51
1.2.1.2.4.2. Particulate matter increases IL-

Inhaled particulate matter increased gene expression for IL-1β in mice.83
Particulate matter also increases the risk of ADHD.

1.2.1.3. IL-1-Ra

Interleukin 1 receptor antagonist

IL-1Ra (as well as anti-inflammatory cytokines such as IL-10) prevents the symptoms mediated by IL-1. IL-1-Ra prevents the reduction of social behavior by IL-1beta, but not the reduction of body weight by IL-1beta in rats.84

Alcohol consumption (to 1.2 per mille) increases the IL-1Ra values within 2 hours and for at least another 10 hours, while the alcohol was completely broken down within 10 hours.50

High IL-6, IL-1beta and IL-1-RA levels correlate with reduced connectivity between

  • Striatum and vmPFC 75

In response to mild stress, healthy subjects with a low cortisol stress response showed higher stress responses of IL-6 and IL-1ra in the blood than those with a high cortisol stress response. At the same time, subjects with a low cortisol stress response showed lower heart rate variability, indicating poorer stress processing by the autonomic nervous system.85 ADHD-HI is often associated with a flattened cortisol stress response, while ADHD-I is very often associated with an elevated cortisol stress response.

1.2.2. IL-2

Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte-LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the non-stressed state.
Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.51

1.2.2.1. Neurophysiological effects of IL-2
1.2.2.1.1. IL-2 increases the turnover of noradrenaline and dopamine

IL-2 causes an increase in the turnover (which leads to a reduction in the level) of

  • Noradrenaline in the hypothalamus59
  • Noradrenaline in the hippocampus61
  • Dopamine in the PFC5961
  • Dopamine in the striatum86
  • IL-2 in low doses in newborn mice causes reduced dopamine levels in the hypothalamus in adulthood.87
  • Since IL-2 increases the release of dopamine and there are particularly many IL-2 receptors in the hippocampus, IL-2 has an effect on memory function.61
  • The effects of IL-2 on dopamine and noradrenaline are weaker than those of IL-1 and IL-6.1
1.2.2.1.2. No increase in serotonin or cortisol due to IL-2
  • No increase in
    • Serotonin59. Different: moderate increase in serotonin.1
    • Cortisol in the blood59
1.2.2.1.3. IL-2 induces glucocorticoid resistance
  • IL-2 and IL-4 combined induce glucocorticoid resistance in T cells by significantly reducing the affinity of the glucocorticoid receptor for its ligand.88 89 In addition, the conversion of cortisol into less active or inactive metabolites reduces the glucocorticoid sensitivity of immune system cells to glucocorticoids.90
1.2.2.1.4. IL-2 reduces acetylcholine

IL-2 reduces the release of acetylcholine

  • In the hippocampus61
  • In the PFC61
1.2.2.2. Behavioral effects of IL-2

Typical behavioral effects of IL-2 are:61

1.2.2.2.1. Sedating
  • IL-2 has a sedative effect
    • Presumably via the locus coeruleus91
1.2.2.2.2. Motor effects on posture
  • Has motor effects on posture
  • Can trigger schizophrenia symptoms depending on the dose92
1.2.2.2.3. Memory impairment
  • Chronic administration of IL-2 impairs working memory62 and memory function because IL-2 increases the release of dopamine and the hippocampus contains a particularly large number of IL-2 receptors.61
1.2.2.2.4. Anhedonia, impaired motivation
  • IL-2 single dose influences reward processes/motivation (anhedonia), unlike IL-1 beta and TNF alpha62
1.2.2.2.5. Not caused: Anxiety, Anorexia, Sickness behavior
  • Single-dose IL-2 does not trigger anxiety symptoms, unlike IL-1 beta and TNF alpha, which act synergistically62
  • IL-2 does not trigger sickness behavior, unlike IL-1 beta and TNF alpha, which act synergistically62
  • IL-2 does not trigger anorexia, unlike IL-1 beta and TNF alpha, which act synergistically62
1.2.2.3. IL-2 and ADHD

The only cerebrospinal fluid study to date found IL-2 in 90% of children with ADHD.53 One study found no changes in blood serum levels of IL-2, IL-4, IL-17, TNF-α and IFN-gamma in ADHD.54 Cerebrospinal fluid levels are likely to be crucial for behavioral effects.

1.2.2.2.3. IL-2 reduces oppositional defiant behavior, prolongs reaction time

Within a group of children with ADHD, reduced TNF-α and IL-2 plasma levels correlated with higher levels of oppositional defiant behavior, while higher IL-2 plasma levels correlated with reduced reaction time.93

1.2.3. IL-4

1.2.3.1. IL-4 inhibits cytokine-induced depression

The activation of effector T cells (TH cells) during stress can have an inhibitory effect on depressive and anxious behavior in mice by activating IL-4. TH cells in the meninges produce IL-4, which has an anti-inflammatory effect and stimulates the production of growth factors in the brain that support neuronal plasticity and resilience.94

IL-4 and IL-10 inhibit the activity of TH-1 cells and macrophages.49

1.2.3.2. Induces glucocorticoid resistance

IL-2 and IL-4 combined induce glucocorticoid resistance in T cells by significantly reducing the affinity of the glucocorticoid receptor for its ligand.88 89 In addition, the conversion of cortisol into less active or inactive metabolites reduces the glucocorticoid sensitivity of immune system cells to glucocorticoids.90

1.2.3.3. IL-4, stress and behavior

Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte-LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the non-stressed state.
Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.51

1.2.3.4. Serum IL-4 probably not elevated in ADHD

One study found no changes in serum levels of IL-2, IL-4, IL-17, TNF-α and IFNG in ADHD.54

1.2.4. IL-5

1.2.4.1. IL-5 in cerebrospinal fluid often elevated in ADHD

The only examination of cerebrospinal fluid for cytokines in ADHD to date found IL-5 in 62% of children with ADHD.53

1.2.5. IL-6

1.2.5.1. Neurophysiological effects of IL-6
1.2.5.1.1. Increased dopamine and serotonin turnover, noradrenaline and cortisol unchanged
  • IL-6 causes an increase in the turnover (which leads to a reduction in the level) of59
    • Serotonin in the hippocampus and PFC
    • Dopamine in the PFC
    • But not of noradrenaline in the hypothalamus or hippocampus
    • No increase in cortisol in the blood
  • IL-6 increases tryptophan levels and serotonin turnover in the brain (but less so than IL-1), but not noradrenaline.1
  • IL-6 (and TNF-alpha) do not reduce noradrenaline uptake, but the IL-6-related CT-1 does.8
1.2.5.1.1.1. IL-6 and depression
  • IL-6 (and even more so the IL-6-related cardiotrophin-1, CT-1) reduce BH4 levels.8 BH4 is an enzyme required for the synthesis of serotonin, dopamine and noradrenaline. A reduction in BH4 results in reduced serotonin and dopamine levels.
  • IL-6 and sIL-6R (following administration of interferon-alpha) did not correlate with increased depression levels according to the MADRS. Changes in daily IL-6 levels had no effect on behavior.25
  • A strong increase in IL-6 is neurophysiologically associated with95
    • Increased activity within the subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotion appraisal
  • The stress response of TNF-α, IL-6 and CRP is higher in people with depression than in those without.96
1.2.5.1.2. Activation of the HPA axis
  • However, activation of the HPA axis60 is weaker than by IL-1.1
1.2.5.1.3. Increases acute-phase proteins
  • Increase in acute phase proteins97
  • Slowed psychomotor skills98
1.2.5.1.4. Reduced connectivity
  • The strong increase in IL-6 is neurophysiologically associated with95
    • Reduced connectivity of sACC with amygdala, medial prefrontal cortex, nucleus accumbens and superior temporal sulcus, which was modulated by peripheral interleukin-6
  • High IL-6, IL-1beta and IL-1-RA levels correlate with reduced connectivity between
    • Striatum and vmPFC 75
1.2.5.1.5. IL-6 reduces Il-1 and TNF
  • IL-6 reduces the production of IL-1 and TNF-α in the blood by phagocytes.99
1.2.5.2. Behavioral changes due to IL-6
1.2.5.2.1. Fever, Sickness Behavior
  • Fever
    • As well as IL-1 and TNF56
  • Sickness behavior
    • Reduced food intake97
    • Reduced water absorption
    • Trembling
    • Increased drowsiness
    • Reduced social interest
1.2.5.2.2. Anhedonia, increased fear of loss
  • Reduced response to rewards (anhedonia), increased fear of loss/punishment100
1.2.5.2.3. Drop in mood

IL-6 mediates a deterioration in mood.95100

1.2.5.2.3. Reduced reaction speed

IL-6 causes prolonged reaction times.101102

1.2.5.2.3. Cognitive performance under stress

IL-6 mediates impairment of cognitive performance during stress. The higher the IL-1β, IL-6, and IL-8 stress response to an emotionally stressful movie, the greater the stress-induced impairment of cognitive control/performance in the Stroop test.76

1.2.5.2.3. Competitive and negative social behavior

IL-6 causes increased competitive social interactions. The basal blood levels of IL-6 and the soluble TNF receptor correlate with the level of competitive social interactions.103 Competitive social interactions are the opposite of cooperation.

IL-6 causes increased negative social interactions. The IL-6 and soluble TNF receptor stress response correlated positively with the level of negative social interactions. The basal blood level of the soluble TNF receptor correlated positively with the level of negative social interactions.103 Aggression is an example of negative social interaction.

Psychological stress (through TSST such as Angry memory retrieval) leads to an increase in IL-6 (as well as IL-1β and TNF-α) in the sense of a stress response. The stress-induced increase in IL-6, IL-1β and TNF-α correlated with negative emotions.79

1.2.5.3. IL-6 in serum: correlation to ADHD questionable

A study of 135 unmedicated adults found no differences in IL-6 in the blood between ADHD-HI sufferers, ADHD-I sufferers and non-sufferers.104 Another study of 2307 participants in a Dutch study came to the same conclusion.105

Another study of 120 children with and without ADHD found on average 4-fold higher serum IL-6 levels in the children with ADHD, with no correlation with IQ or symptom severity.106
Compared to the other studies, the same analysis technique was used, only from a different manufacturer.
Another study also found increased IL-6 and IL-10 serum levels in children with ADHD.54

The different results could possibly be due to the fact that the levels of IL-6 in the blood and in the cerebrospinal fluid do not necessarily correlate and that neuropsychological effects of the cytokines are not represented by blood levels of the same.73

1.2.5.4. Causes of an increase in IL-6: stress / infections
  • Stress hormones increase IL-6:107
    • Noradrenaline
    • CRH
  • Noradrenaline, which (like cortisol) is part of the endocrine stress response, stimulates the expression of IL-6 mRNA and the production of IL-6 in astrocytes via β2 and α1 adrenoceptors in a dose-dependent manner.108 Since the release of noradrenaline occurs before the activation of the HPA axis, the inhibition of IL-6 by cortisol could represent a negative feedback loop, comparable to the inhibition of the HPA axis after a stress response.
  • Stress in the mother, which causes damage to the unborn child, is presumably primarily mediated by IL-6. The inadequate development of GABAergic cells in the unborn child caused by prenatal stress in the mother can apparently be prevented by IL-6 antagonists.109
  • Psychological stress (TSST as well as angry memory retrieval) led to an increase in IL-1β, TNF-α and IL-6 in the sense of a stress response. The stress-induced increase in IL-1β, TNF-α and IL-6 correlated with negative emotions.79
  • On habituation to the stressor, the cortisol stress response decreased, but apparently not (or more slowly?) the IL-6 stress response.110
  • The stress response of TNF-α, IL-6 and CRP was higher in people with depression than in those without.96
  • IL-6, IL-10, IL-17, IFN-γ and TNF-α were little affected by alcohol consumption (to 1.2 per mille).50
  • In response to mild stress, healthy subjects with a low cortisol stress response showed higher stress responses of IL-6 and IL-1ra in the blood than those with a high cortisol stress response. At the same time, subjects with a low cortisol stress response showed lower heart rate variability, indicating poorer stress processing by the autonomic nervous system.85 ADHD-HI is associated with a flattened cortisol stress response, while ADHD-I is associated with an elevated cortisol stress response.
  • A thyphoid vaccination led to a 250% increase in IL-6, which correlated with a drop in mood. The group that was not vaccinated against thyphoid but treated with placebo showed a slight increase in IL-6 of 30%.100 This could be due to the stress associated with the test.
  • Particulate matter did not increase the gene expression for IL-6.83
1.2.5.5. Influencing IL-6

An administration of 635 mg eicosapentaenoic acid (EPA) and 195 mg docosahexaenoic acid (DHA) (unsaturated fatty acids) reduced serum CRP and IL-6 levels in children with ADHD and improved ADHD symptoms within 8 weeks in a double-blind placebo study.111

1.2.6. Cardiotrophin-1 (CT-1)

Cardiotrophin-1 is a cytokine from the IL-6 protein family.

  • CT-1 (and, to a lesser extent, IL-6) reduces BH4 levels.8
  • CT-1 (but not IL-6 or TNF-alpha) reduces noradrenaline uptake.8

1.2.7. IL-8

The higher the IL-8, IL-1β and IL-6 stress response to an emotionally stressful movie, the greater the stress-related impairment of cognitive control/performance in the Stroop test.76

1.2.8. IL-10

  • IL-10 increases the performance of the DSST (Digit Symbol Substitution Task).102
  • Elevated IL-10 levels correlate with a tendency to allergies.112
  • IL-10 and IL-4 inhibit the activity of TH-1 cells.49
1.2.8.1. Causes of IL-10: Stress
  • Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte-LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the non-stressed state.
    Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.51
  • In women, stress caused by an interview led to an increase in81
    • Plasma cortisol
    • Noradrenaline
    • IL-
    • IL-10
    • TNF-a
    • Number and activity of natural killer cells.
  • IL-10, IL-6, IL-17, IFN-γ and TNF-α are little affected by alcohol consumption (to 1.2 per mille).50
1.2.8.1. IL-10 for ADHD

Elevated IL-10 plasma levels correlate with higher ADHD symptoms93 Another study also found elevated IL-6 and IL-10 serum levels in children with ADHD.54
The only examination of cerebrospinal fluid for cytokines in ADHD to date found IL-10 in 7% of children with ADHD.53

1.2.9. IL-12

IL-12 and IFN-γ inhibit the activity of TH-2 cells.49
IL-12 strongly promotes IFN-γ.49
IL-12 strongly inhibits IL-4 production by T cells.49

1.2.10. IL-13

1.2.10.1. IL-13 in ADHD

IL-13 is an anti-inflammatory cytokine. Elevated plasma IL-13 levels tend to correlate with increased inattention.93

1.2.12. IL-16

Elevated IL-16 levels correlate with allergy susceptibility112

1.2.12.1. IL-16 for ADHD

Elevated IL-16 plasma levels correlate with higher ADHD symptoms and increased hyperactivity/impulsivity.93 Higher IL-16 plasma levels also correlate with higher commission errors.93

1.2.13. IL-17

IL-6, IL-10, IL-17, IFN-γ And TNF-α are little affected by alcohol consumption (to 1.2 per mille).50

1.2.13.1. IL-17 - no known correlation to ADHD

One study found no changes in serum levels of IL-2, IL-4, IL-17, TNF-α and IFNG.54

1.3. Tumor necrosis factor

1.3.1. TNF

1.3.1.1. Neurophysiological effect of TNF
1.3.1.1.1. Only high doses reduce serotonin and noradrenaline

TNF-alpha increased the activity of the serotonin transporter, which leads to increased degradation of serotonin.67

TNF-α only addresses noradrenaline and tryptophan at high doses.1

A single administration of TNF-α or IL-1-b does not alter the release of noradrenaline in sympathetic cells.113

  • A renewed depolarization after 6 minutes reduced the release of noradrenaline
  • A renewed depolarization after 10 minutes restored the release of noradrenaline
1.3.1.1.2. HPA axis activation

TNF-α activates the HPA axis97 as well as IL-6.1

1.3.1.1.3. Acute phase proteins increased

TNF-α leads to increased acute phase proteins.97

  • TNF-α causes sensitization for subsequent new TNF-α administration62
1.3.1.1.3. TNF-α inhibits allergies

Reduced TNF-α levels correlated with allergies.112

1.3.1.2. Behavioral changes due to TNF
1.3.1.2.1. Fever and sickness behavior
    • Fever56
      • Sickness behavior
        • As well as IL-1 beta, unlike IL-2 single dose62
        • Reduced food intake60
        • Reduced water absorption
        • Trembling
        • Increased drowsiness
        • Reduced social interest.
1.3.1.2.2. Fear

TNF-α triggers anxiety symptoms, as does IL-1- beta, unlike single-dose IL-2.62

1.3.1.2.3. Anorexia

TNF-α triggers anorexia, as does IL-1 beta, unlike IL-2 single dose62

1.3.1.2.4. TNF-α inhibits oppositional defiant behavior

Within a group of children with ADHD, reduced TNF-α and IL-2 plasma levels correlated with higher levels of oppositional defiant behavior.112

1.3.1.2.5. Conditional influence on depression

Increased TNF-α and TNFR2 values after IFN-α administration correlated significantly with increased depression values according to the MADRS.25 Treatment of patients with treatment-resistant depression with a TNF antagonist was only helpful with high basal hs-CRP levels above 5mg/L and high TNF-α levels.114

1.3.1.2.6. No influence on anhedonia and motivation

TNF-α has no known influence on reward processes / motivation (anhedonia), nor does IL-1- beta, unlike a single dose of IL-2.62

1.3.1.3. TNF-α in serum: no correlation to ADHD

A study of 135 unmedicated adults found no differences in TNF-α in the blood between ADHD-HI sufferers, ADHD-I sufferers and non-sufferers.104 A study of 2307 participants in a Dutch study came to the same conclusion.105 One study found no changes in serum levels of IL-2, IL-4, IL-17, TNF-α and IFN-gamma in children with ADHD.54

Whether this could be due to the fact that the levels of TNF-α in the blood and in the cerebrospinal fluid can be different and neuropsychological effects of the cytokines are not represented by their blood levels but by their levels in the brain,73 is an open question.

1.3.1.4. Effects on TNF
1.3.1.4.1. Stress increases TNF
  • Psychological stress (TSST such as angry memory retrieval) leads to an increase in IL-1β, TNF-α and IL-6 in the sense of a stress response. The stress-related increase in IL-1β, TNF-α and IL-6 correlates with negative emotions.79 Likewise for TNF-α.110
  • Stress causes an increase in cortisol and TNF-α (stress response).96110 Another study confirms this for IL-1-b and TNF-α and, to a lesser extent, for CRP.80
  • The stress response of TNF-α, IL-6 and CRP is higher in people with depression than in those without.96
  • In women, stress caused by an interview led to an increase in81
    • Plasma cortisol
    • Noradrenaline
    • IL-
    • IL-10
    • TNF
    • Number and activity of natural killer cells
  • In women, stress caused by sleep deprivation led to an increase in82
    • IL-
    • TNF
    • Natural killer cells.
1.3.1.4.2. Particulate matter increases TNF

Inhaled particulate matter was found in the brain tissue of mice, where it increased the level of TNF63 by upregulating the responsible gene.83

1.3.1.4.3. Alcohol does not change TNF

TNF-α, IL-6, IL-10, IL-17 and IFN-γ were little affected by alcohol consumption (to 1.2 per mille).50

1.3.1.4.4. TNF-α - blocker

TNF-α blockers inhibit the inflammatory processes mediated by TNF-α.
The annual therapy costs of a treatment amount to around €40,000 (as of 2019).

  • Etanercept
    • Receptor fusion protein, first approved in 2003.
  • Adalimumab
    • Fully human monoclonal antibody, first approval in 2006.

1.3.2. TNF

1.3.2.1. TNF-β in cerebrospinal fluid: high correlation to ADHD

The only study to date of cerebrospinal fluid in children with ADHD found TNF-β in 70%.53

1.3.3. TNFR2

TFNR2 does not show a daily rhythm.25
IFN-α 2a and IFN-α 2b lead to significantly increased TFNR2 levels.25
The increase in TNF-α and TNFR2 to IFN-α correlated significantly with increased depression scores after the MADRS.25

1.4. Chemokines

1.4.1. MCP-1

MCP-1 (monocyte chemoattractant protein 1) reduced performance on psychomotor tasks such as a finger-tapping task and the DSST (Digit Symbol Substitution Task).102
Alcohol consumption (to 1.2 per mille) initially reduces the value of the chemokine MCP-1 acutely, whereby this increased steadily over the following 12 hours and remained above the initial value, while the alcohol was completely broken down within 10 hours.50
MCP-1 correlated with slower psychomotor skills.98

1.4.2. CCL5 (RANTES), CXCL8 (= IL-8, NAP-1, MDNCF, GCP-1)

In ASD patients, significant associations were found between increased plasma levels of CCL5 (= RANTES) and CXCL8 (= IL-8, NAP-1, MDNCF, GCP-1) and more frequent abnormal behaviors and less adaptive behaviors.115116117

1.5. TGFβ1 (transforming growth factor)

TGF is a cytokine.

A reduced plasma level of TGFβ1 (transforming growth factor beta1) correlated with more stereotypy, irritability, hyperactivity and other behavioral symptoms and less adaptive behavior in a study of people with ASD.118

2. Other inflammatory markers

2.1. NF-kB (Nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells)

NF-kB is a specific transcription factor that occurs in almost all animal cell types and tissues. By binding to regulatory sections of DNA, it can influence the transcription of dependent genes.
Psychosocial stress increases NF-kB levels in peripheral human blood cells via noradrenaline at alpha(1) and beta adrenoceptors. The stress also increased catecholamines and cortisol. NF-kB returned to baseline levels after one hour.119
Inhaled particulate matter was found in the brain tissue of mice and increased the NF-kB level there.63

In chronic autoimmune rheumatic diseases, adenosine A2A and A3 receptors are overexpressed in lymphocytes. A2A and A3 agonists inhibited the activation of NF-κB, the release of typical proinflammatory cytokines and the concentration of metalloproteinases, which are involved in the inflammatory reactions in chronic autoimmune rheumatic diseases.120

2.2. MIF / MMIF / GIF

MIF / MMIF (macrophage migration inhibitory factor) is also known as GIF (glycosylation-inhibiting factor), L-dopachrome isomerase or phenylpyruvate tautomerase. It is a pro-inflammatory cytokine.
Elevated plasma levels of MIF correlate with more severe social impairments and less imaginative play in people with ASD, according to a study.121

2.3. C-reactive protein (CRP)

CRP is an acute phase protein. It activates the complement system.
High CRP values

  • Correlate with reduced connectivity between75
    • Ventral striatum and ventromedial prefrontal cortex (vmPFC),
      • This correlated with
        • Increased anhedonia
    • Between dorsal striatum, vmPFC and presupplementary motor cortex
      • This correlated with
        • Reduced motor activity
        • Increased psychomotor deceleration
    • Striatum and vmPFC are parts of the (mesocorticolimbic) dopaminergically controlled reward system.10
  • High IL-6, IL-1beta and IL-1-RA levels also correlate with reduced connectivity between
    • Striatum and vmPFC 75
  • Elevated cerebrospinal fluid CRP correlates significantly with elevated glutamate levels in the right basal ganglia, independent of age, gender, race, body mass index, smoking status, and depression severity.24
  • Increased glutamate in the right basal ganglia correlates with anhedonia and psychomotor slowing in various tests.24
  • Plasma CRP did not correlate with glutamate levels in the dorsal ACC.24
  • CRP in plasma and CSF correlate with CSI measurements of basal ganglia glutamate and the glial marker myoinositol.24
  • Acute stress increases the blood levels of IL-1-b and TNF-a and, to a lesser extent, CRP.80
  • The stress response of TNF-α, IL-6 and CRP is higher in people with depression than in those without.96

2.3.1. CRP in serum: no correlation to ADHD

A study of 2307 participants in a Dutch study found no correlation between blood levels of C-reactive protein (CRP) and ADHD-C.105
In a double-blind placebo study, the administration of 635 mg eicosapentaenoic acid (EPA) and 195 mg docosahexaenoic acid (DHA) (unsaturated fatty acids) reduced serum CRP and IL-6 levels in children with ADHD within 8 weeks and improved ADHD symptoms.111

2.4. Natural killer cells

In women, stress caused by sleep deprivation led to an increase in82

  • Natural killer cells
  • IL-
  • TNF

3. Oxidative stress

3.1. Oxidative stress in ADHD

In ADHD, the serum

  • Significantly increased values of
    • Nitric oxide synthase (NOS),
    • Xanthine oxidase (XO),
    • Adenosine deaminase (ADA)
  • And significantly reduced values of
    • Glutathione S-transferase (GST)
    • Paraoxonase-1 (PON-1)

found. No differences were found between ADHD-HI and ADHD-I.
NOS, XO, GST and PON-1 are important markers for oxidative stress. ADA is a marker for cellular immunity.122

4. Consequences of infection

4.1. Endotoxin / lipopolysaccharide (LPS)

Endotoxin / lipopolysaccharide (LPS) is a pathogen excreted by the bacterium Escherichia coli (E. coli). Infections with E. coli are therefore a trigger for a severe immune reaction.

4.1.1. Neurophysiological effects of endotoxin

4.1.1.1. Noradrenaline, serotonin turnover increased by endotoxin

Endotoxin / lipopolysaccharide (LPS) increases noradrenaline and serotonin turnover and tryptophan levels, as does IL-1. IL-1 antagonists partially prevent this effect.1

4.1.1.2. Dopamine reduced by endotoxin
  • The same low dose of endotoxin that makes sugar rewards less interesting appears to decrease dopamine and serotonin in the nucleus accumbens123 and significantly increase metabolites of catecholamines, such as 5-HIAA, DOPAC and HVA, in the nucleus accumbens and mPFC. The fact that a reuptake inhibitor was able to prevent this effect indicates that endotoxin increases the activity of the DAT.124
  • Both the short- and long-term effects of endotoxin on dopamine levels can be neutralized by inhibition or genetic blockade of inflammatory cytokines such as TNF-α (e.g. by Catalpol).124125 This suggests that TNF-α (among others) may mediate anhedonia.
  • Endotoxin reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (a site of origin of dopamine)126
    • 7 months after treatment by 23 %127
    • By 47 % 10 months after treatment127
4.1.1.3. Effects of endotoxin on cytokines
  • Increases IL-1-1
    • Increases the expression of IL-1-beta (except in mice with deactivated TNFα receptor):127
  • Increases IL-61
    • If the sensitivity for suppression of the HPA axis by dexamethasone is reduced, endotoxin causes significantly stronger increases in IL-6.128
  • Increases IL-10
    • Cortisol administration immediately before endotoxin administration significantly increased the IL-10 increase. Cortisol administration more than 6 hours before endotoxin administration did not affect the IL-10 increase. In the laboratory, cortisol reduced the endotoxin-induced IL-10 increase and reversed the adrenaline-induced IL-10 increase to an IL-10 decrease upon endotoxin administration.129
  • Increases TNF
    • Cortisol administration immediately before endotoxin administration prevents TNFrelease. Cortisol administration more than 12 hours before endotoxin administration increases the TNF-α increase caused by endotoxin.1291
    • A single administration of endotoxin in mice immediately increases the TNF-α level (except in mice with deactivated TNFα receptor). While the peripheral TNF-α level decreased in the serum after 9 h and in the liver after 1 week, it was still elevated in the brain after 10 months.127
    • If the sensitivity for suppression of the HPA axis by dexamethasone is reduced, endotoxin causes significantly stronger increases in TNFα.128
  • Increases MCP-1
    • Endotoxin increases the expression of MCP-1 (except in mice with deactivated TNFα receptor):127
  • Increases NF-κB p65
    • Endotoxin increases the expression of NF-κB p65 (except in mice with deactivated TNFα receptor):127
4.1.1.3. Endotoxin activates microglia

Endotoxin-activated microglia (as well as TNF-α)126 (except in mice with deactivated TNFα receptor)127 microglia can increase the expression of inducible nitric oxide synthase (iNOS) and release significant amounts of nitric oxide (NO) and TNF-α, which can damage dopaminergic neurons.125

4.1.1.4. Endotoxin increases cortisol

If the sensitivity for suppression of the HPA axis by dexamethasone is reduced, endotoxin causes significantly stronger increases in cortisol.128

4.1.2. Behavioral changes due to endotoxin

4.1.2.1. Endotoxin increases depressive mood

Endotoxin increases the depressive mood1301 within 24 hours.131
Peripheral endotoxin triggers depressive behavior via indoleamine 2,3-dioxygenase (IDO) by increasing tryptophan turnover. The degradation substance of tryptophan, L-kynurenine, triggers depressive behavior in a dose-dependent manner.132

  • An IDO blockade before endotoxin administration
    • Prevents depressive behavior.
    • Normalizes the kynurenine/tryptophan ratio in plasma and brain
    • Does not prevent the increase in serotonin turnover in the brain
  • IDO can be blocked
    • Indirectly through anti-inflammatory drugs that attenuate the expression of pro-inflammatory cytokines induced by endotoxins, e.g. minocycline (a broad-spectrum antibiotic that increases COX-2)133
    • Directly through IDO antagonists, e.g. 1-methyltryptophan (1-MT)

Endotoxin131

    • motor activity still decreased after 6 hours, but no longer after 24 hours
      • Increased depressive and anhedonic behavior even after 24 and 48 hours
      • After 6 hours, c-Fos was significantly reduced in all brain areas
      • After 24 hours, depressive behavior correlated with delayed cellular activity (FosB/ΔFosB), particularly in the amygdala, hippocampus and hypothalamus
4.1.2.2. Anhedonia increased

Endotoxin reduces the activity of the striatum to offered rewards (anhedonia).130 It reduced the motivation to develop activities to obtain sugar rewards, while the preference for sugar over other food itself was not reduced.134123

4.1.2.3. Reduced motor activity

Endotoxin131

    • motor activity still decreased after 6 hours, but no longer after 24 hours
      • Increased depressive and anhedonic behavior even after 24 and 48 hours
4.1.2.4. Lifelong behavioral changes with endotoxin in newborns
4.1.2.4.1. Reduced depression symptoms in response to stress with unchanged serotonin levels

Newborn rats treated with endotoxin showed lower depressive symptoms in response to inescapable pain stress than adult animals.135 The serotonin level in the amygdala did not differ before, during or after the stress from the animals that were not treated with endotoxin as newborns.

4.1.2.4.2. Flattened cortisol stress responses

While the basal cortisol levels of the newborn rats before endotoxin treatment and also of the adult animals of both groups did not differ, adult animals treated with endotoxin as newborns showed a significantly flattened cortisol stress response during and after the stress.135

4.1.2.4.3. Memory problems with renewed immune activation in adulthood

Neonatal rats treated with endotoxin respond to repeated endotoxin treatment in adulthood77

  • Increased gene expression for microglia cell markers in the hippocampus
  • A stronger increase in the gene expression of glial cell markers in the hippocampus
    • This increase remained elevated for 24 h longer
  • A faster increase in IL-1beta in the hippocampus and PFC
  • A prolonged increase in IL-1-beta in the PFC
  • Peripheral cytokines or basal corticosterone were unchanged
  • Impaired memory
    • This could be prevented by administering a caspase-1 inhibitor to the adult animals 1 hour before the learning event and subsequent endotoxin administration.
      A caspase-1 inhibitor prevents the synthesis of IL-1beta
4.1.2.4.4. Reduced immunological effect of amphetamine

Endotoxin in newborn rats on day 4 of life causes altered responses to amphetamines in juvenile animals. The effects on were investigated:136

  • Proinflammatory cytokines:
    • IL-
    • IL-6
    • TNFα
  • Anti-inflammatory cytokines:
    • IL-10
  • CD200 (anti-inflammatory neuroimmune regulatory molecule)
  • ARC (Activity-Regulated Cytoskeleton-Associated Protein)
  • CD11b (a microglial membrane protein)
  • GFAP (glial fibrillary acid protein, an astroglia marker)

The changes caused by a single non-intoxicating dose of amphetamine in juvenile animals differed according to brain region:

Changes in the PFC:

In the mPFC, amphetamine increased the gene expression for

  • IL1β
  • IL6
  • TNFα
  • CD200
  • Arc
  • GFAP

in rats that were not treated neonatally with endotoxin, but not in animals that were treated with endotoxin on day 4 of life.
There were no relevant differences for CD11b and IL-10.

Changes in the nucleus accumbens:

In the NAcc, amphetamine increased the gene expression for

  • IL1β
  • CD200

only in rats not treated with endotoxin,
while gene expression decreased from

  • CD200

only in animals treated with endotoxin.

In all animals, amphetamine increased the gene expression of

  • IL1β
  • Arc

The following remained unchanged

  • IL6
  • GFAP
  • CD11b
  • IL-10
  • TNFα

Changes in the hippocampus (CA1):

Amphetamine increased the gene expression for

  • Arc
  • GFAP

only in rats not treated with endotoxin

Amphetamine increased the gene expression of

  • IL1β

for all animals.

The following remained unchanged

  • IL6
  • CD200
  • CD11b
  • IL-10
  • TNFα.

Thus, these results are more similar to the effects of neonatal E. coli infection on the adults’ response to psychological stress, which were blunted, than on the adults’ response to LPS, which were enhanced.

5. Other elements inside and outside the immune response

5.1. BDNF

5.1.1. BDNF in serum: rather no correlation to ADHD

BDNF is not an inflammatory marker, but is relevant for neurogenesis.

One study found significantly reduced levels of BDNF (brain-derived neurotrophic factor) in the blood of adults with ADHD, although these levels tended to be even lower in ADHD-HI than in ADHD-I.137 In contrast, another study found increased BDNF levels in children with ADHD.138
However, a study of 2307 participants in a Dutch study139 and another study140 found no correlation between blood levels of the growth factor BDNF and ADHD.

5.2. Intercellular adhesion molecule-3

Cell adhesion molecules (CAM) are proteins that mediate contact between cells in tissue. They bring about the cohesion of tissues and communication between cells.

In extremely premature infants, a one-day increase in intercellular adhesion molecule-3 increased the risk of attention problems.141
In extremely preterm infants, the risk of attention problems increased with the detection of persistent or recurrent elevations of141

  • Myeloperoxidase
  • Interleukin-6
  • TNF-RI
  • IL-8
  • Intercellular adhesion molecule-3
  • Vascular endothelial growth factor-R1
  • Vascular endothelial growth factor-R2

5.3. Anti-Yo antibody

Anti-Yo antibodies are immunoglobulin G (IgG) autoantibodies that react with a 62 kDa Purkinje cell cytoplasmic protein. They impair the function of the cerebellum (small brain).142 The cerebellum is responsible for motor coordination. Motor problems are common in ADHD.143

One study found anti-Yo antibodies in 77.5% of children with ADHD. The IL-6 and IL-10 plasma levels were also elevated in these children.144

5.4. S 100 B

5.4.1. S 100 B reduced for ADHD-I

S100B is a cytokine-related neurotrophin. Diagnostically, S-100B is a marker for brain damage (e.g. stroke, craniocerebral trauma).

Children with ADHD and predominantly internalizing symptoms (ADHD-I) showed lower S100B plasma levels than ADHD children with externalizing symptoms (ADHD-HI).93

5.5. C4B-binding protein (C4BP)

C4BP is an (inhibitory) regulator of the complement system.

5.5.1. C4BP for ADHD

Reduced C4BP blood levels were found in ADHD sufferers and their mothers (but not their fathers). C4BP is a protein that is important for the immunological defense against viral and bacterial infections by the complement system.145

5.6. GAD65 antibody

5.6.1. GAD65 antibodies in ADHD and ASD

Antibodies against glutamic acid decarboxylase 65 (GAD65) were found in the serum of 15 % of the children with autism (N = 20), 27 % of the children with ADHD (N = 15) and none of the controls (N = 14). The serum of 60 % of the autistic children and 53 % of the children with ADHD reacted with Purkinje neurons in the mouse cerebellum. The serum of 20% of the children with ADHD also reacted with the cells in the molecular and granular cell layers and cells in the vicinity of the Purkinje neurons. Reactions of serum antibodies with the cells in the cerebellum indicate direct effects on brain function.146


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