Cytokine

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Cytokines are any class of immunoregulatory proteins secreted by cells, especially immune system cells.[1] Cytokines are small proteins important in cell signaling that modulate the immune system.

There are many different cytokines. They function as messenger molecules passing information around the body. They resemble hormones in this way, but they are usually communicating in response to something external and lead to inflammatory or immune responses.

Types of cytokines[edit | edit source]

Cellular immune response[edit | edit source]

IFN-γ, TNFα

Antibody response[edit | edit source]

TGF-β, IL-4, IL-10, IL-13

Role in human disease[edit | edit source]

Chronic Fatigue Syndrome[edit | edit source]

There is increasing evidence that cytokine expression is altered in CFS (ME). Mady Hornig et al (2015) indicates that there is a generally increased response in the first 3 years of illness.[2] In 2017, a Montoya, et al, study showed that "seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity"..."thirteen of these are proinflammatory, likely contributing to many of the symptoms experienced by patients."[3]

Two large 2015 studies found a general pattern of down regulation in long term patients (Hornig, et al and Landi, et al). [4] It is worth noting that these differences can average each other out when data from newly diagnosed and long term patients are analysed together. More accurate data may necessitate patient groups being stratified by disease duration.

In a 2017 study by Hornig, Lipkin et al, 51 Cytokines of cerebrospinal fluid were measured where they found Atypical and Classical cases of ME/CFS. There are differing immune signatures within the central nervous system. "Typically, symptoms of ME/CFS begin suddenly following a flu-like infection, but a subset of cases classified by the investigators as “atypical” follows a different disease course, either from triggers preceding symptoms by months or years, or accompanied by the later development of additional serious illnesses."[5]

When reading cytokine studies it is important to remember that with so many cytokines it is common to find some pattern and results can change quickly within individuals. In a small sample, if just a couple of people were fighting a cold then this could change the overall results.

Fibromyalgia[edit | edit source]

Fibromyalgia: Cytokines IL-1beta, IL-6 and TNF-alpha are involved with central and peripheral neuropathic pain which is experienced by Fibromyalgia patients.[6] Profiles are distinguishing Lupus and Rheumatoid Arthritis from Fibromyalgia.[7]

Table of Cytokines[edit | edit source]

Cytokine Description Increased in ME/CFS Decreased in ME/CFS
Interferons Interferons are antiviral agents that modulate the immune system. They stimulate Natural killer cells and macrophages to elicit antiviral and anti-tumor responses.
IFN-α (Interferon alpha)

A type I interferon produced by Leucocytes. Major contributor to innate immunity against viral infection.

Increased[8][9]
IFN-β (Interferon beta)

A type I interferon produced in fibroblasts by RNAseL. It is used to reduce relapses in relapsing-remitting multiple sclerosis. Major contributor to innate immunity against viral infection.

IFN-κ (Interferon kappa)

A type I interferon

IFN-γ (Interferon gamma)

The only Type II interferon in humans, it is produced by T cells and natural killer cells. Critical to both innate and adaptive immunity. Promotes macrophage activation.

Increased[10][11][12][13]

Increased in severe illness[14]

Increased with illness severity[3]

Increased in early illness[2]

Decreased[15]

Decreased IFN-γ/IL-10 ratio[16]

Decreased secretion from MAIT cells[17]

IFN-λ (Interferon lambda)

Type III interferon. Immunity response against early stages of viral infection.

Interleukins Promote the growth of immune system cells and help regulate the immune system
IL-1 (Interleukin 1 subgroups: IL-1β, IL-1α)

Regulates immune and inflammatory response, and activates antigen presenting cells

Acts as a major mediator in central fatigue pathways[18]

Elevation of IL-1 in the brain contributes “sickness behavior".[19]

IL-1β is a pro-inflammatory cytokine with metabolic and immuno-inflammatory functions.[14]

Increased IL-1α[20][21][22][23]

Increased IL-1α in females[24]

Increased IL-1β[22][25][23][26][15]

Increased IL-1β, proportional to poor sleep quality[27]

Increased IL-1α in early illness[28][2]

Increased IL-1RA in early illness[2]

Increased in those with 5-HT autoimmune activity[29]

Decreased IL-1β in severe illness[14]

Decreased IL-1β[30]

Decreased IL-1α and IL-1RA in later illness[2]

Decreased in later illness[28]

IL-2 (Interleukin 2)

Stimulates T-Cell growth, regulates immune system, controls cellular proliferation and differentiation

Increased[31][11][32][13][12]

Increased in males[24]

Depressed response post-exercise (increased in controls)[33]
IL-3 (Interleukin 3)

Regulates blood-cell production

IL-4 (Interleukin 4)

Induces naive helper T cells to develop into Th2 cells. Regulates immune system

Increased in early illness[2]

Increased[21][22][13]

Increased with illness severity[3]

Decreased in females[24]
IL-5 (Interleukin 5)

Regulates eosinophils in the bone marrow during inflammation

Increased[22]

Increased with illness severity[3]

Decreased[30][13]
IL-6 (Interleukin 6)

Regulates immune system, cellular proliferation and differentiation, and autoantibody production

An important inflammatory cytokine and HPA axis modulator. IL-6 also plays a role in other CFS symptoms including hyperalgesia, fatigue, sleep impairment, and depression.

It has been reported that IL-6 induces excessive daytime sleepiness or disturbed non-refreshing sleep in patients with CFS, and that increased levels are associated with a decrease in sleep quality.[34]

IL-6 also directly increases glucose metabolism in human skeletal muscle[35]

Increased[22][32][26][13][36][12]

Increased sIL-6R[21]

Increased, proportional to poor sleep quality[27][37]

Increased LIF with illness severity[3]

Increased in early illness[2]

Increased in later illness[28]

Decreased[16][30][15]

Decreased in moderate illness[14]

Decreased LIF[30]

Decreased in early illness[28]

Decreased in later illness[2]

Depressed response post-exercise (increased in controls)[38]

Depressed response to LIF post-exercise (increased in controls)[33]

IL-7 (Interleukin 7)

Regulates adaptive immune system, and tumor cell apoptosis

Increased with illness severity[3][14] Decreased in later illness[4]
IL-8 (Interleukin 8 or CXCL8 C-X-C motif chemokine ligand 8)

Regulates inflammatory response by orchestrating the migration of primarily neutrophils to the site of infection. IL-8 has also been shown to be involved in cell proliferation, and tissue remodeling[39]

Increased[40][41]

Increased in severe illness[14][15]

Increased in sudden onset illness[42]

Increased in early illness[28]

Increased in later illness[2]

Decreased[22][30]

Decreased post-exercise[33]

Decreased in later illness[28]

Decreased in early illness[2]

IL-9 (Interleukin 9)

Promotes mast cell growth, stimulates cell proliferation and cytotoxicity, and is involved in apoptosis

Decreased[13]
IL-10 (Interleukin 10)

Regulates anti-inflammatory response and immune response to pathogens

Increased[10][43][15][13][44]

Increased in abnormal spinal fluid patients[42]

Increased at baseline (measurement 1)[11]

Increased IL-10 and decreased IFN-γ/IL-10 ratio[16]

Decreased[45][30][46]

Decreased at 6 months (measurement 2)[11]

IL-11 (Interleukin 11)

Regulates inflammation, and function of B-cells and T-cells.

IL-11 inhibits tissue inflammation[47]

Increased in early illness[2] Decreased in later illness[2]
IL-12 (Interleukin 12)

Regulates Th1 response, as well as activated T-cells, NK cells, and CTLs. IL-12 is a critical link between the innate and adaptive immunity[48]

Increased[22]

Increased IL-12p70 with illness severity[3]

Increased IL-12p70[12]

Increased IL-12p75[13]

Increased IL-12p40 in early illness[2]

Decreased IL-12B[30]

Decreased in later illness[2]

Depressed response to IL-12p40 post-exercise (increased in controls)[33]

Decreased IL-12p40[36]

IL-13 (Interleukin 13)

Regulates immune response (B-cells and monocytes). Involved in Th2 inflammation.[49]

Increased[13]

Increased in early illness[2]

Increased with illness severity[3]

Decreased[22]
IL-15 (Interleukin 15)

Stimulates activity of cytotoxic CD8+ T-cells and NK cells, and increases anti-tumor activities[50]

Decreased[22]
IL-16 (Interleukin 16)

Modulates T-cell activation

Decreased in later illness[4]
IL-17 (Interleukin 17)

IL-17A and IL-17F regulate immune and inflammatory response in local tissue infection

Increased IL-17F with illness severity[3]

Increased IL-17A in early illness[2]

Decreased[11]

Decreased IL-17F[30][13]

Decreased IL-17A in later illness[2]

Depressed response to IL-17F post-exercise (increased in controls)[33]

Decreased secretion from CCR6+ Th17 cells and MAIT cells[17]

IL-23 (Interleukin 23)

Regulates inflammatory autoimmune responses

Increased in males[24] Decreased[40]

Decreased IL-23p40[36]

Tumor Necrosis Factor Regulate inflammatory and immune responses
TNF-α (Tumor Necrosis Factor alpha)

Regulates acute and chronic inflammation[51]

Increased[10][32][25][23][15][36][11][52]

Increased post-exercise[53]

Increased TNF and sTNFR1[21]

Increased, proportional to poor sleep quality[27]

Increased in early illness[2]

Increased in those with 5-HT autoimmune activity[29]

Decreased[16]

Decreased in later illness[2]

Depressed response post-exercise (increased in controls)[33][38]

LT-α (Lymphotoxin alpha - formerly TNF-β tumor necrosis factor-beta)

Regulates innate immune response

Increased[21][22] Decreased[16][30]

Decreased post-exercise[33]

FasL (Fas ligand or CD95L or CD178)

Regulates immune response and apoptosis

Increased in early illness[2] Decreased in later illness[2]
TNFSF10 (TNF superfamily member 10 or TRAIL)

Regulates apoptosis in transformed cells and mostly functional in immune cells[54]

Increased in early illness[2] Decreased in later illness[2]
CD40L (CD40 ligand or CD154)

Regulates immune response

Increased in later illness[2] Decreased in early illness[2]

Decreased[55]

Chemokines Direct cell migration, adhesion and activation
CCL2 (C-C motif chemokine ligand 2)

Regulates inflammatory response

Increased in early illness[2] Decreased in later illness[2]

No change post-exercise, yet change in controls[33]

CCL4 (C-C motif chemokine ligand 4 or MIP-1β)

Regulates inflammatory response

Decreased post-exercise[33]
CCL5 (RANTES) (C-C motif chemokine ligand 5 or RANTES: Regulated on activation, normal T cell expressed and secreted)

Regulates inflammatory response

Increased in moderate illness[14]
CCL11 (C-C motif chemokine ligand 11)

Regulates inflammatory response

Increased[30]

Increased with illness severity[3]

CCL24 (C-C motif chemokine ligand 24 or eotaxin-2) Increased in later illness[4]
CXCL1 (C-X-C motif chemokine ligand 1)

Regulates immune response via neutrophils[56]

Increased with illness severity[3]
CX3CL1 (C-X3-C motif chemokine ligand 1 or fractalkine) Decreased in later illness[4]
CXCL9 (C-X-C motif chemokine ligand 9) Decreased in later illness[4]
CXCL10 (C-X-C motif chemokine ligand 10 or IP-10)

Regulates immune response via T cells, eosinophils, monocytes and NK cells[57]

Increased[30][12]

Increased with illness severity[3]

Increased post-exercise[33]

Decreased[36]
Colony Stimulating Factors Promote cell proliferation and differentiation
CSF1 (Colony stimulating factor 1 or M-CSF macrophage colony-stimulating factor)

Regulates innate immunity and inflammatory response. Controls cellular proliferation and differentiation of monocytes and macrophages[58]

Decreased[30]
CSF2 (Colony stimulating factor 2 or GM-CSF granulocyte-macrophage colony-stimulating factor)

Controls cellular proliferation and differentiation of granulocytes and macrophages[59]

Increased[12]

Increased with illness severity[3]

Decreased[30]
CSF3 (Colony stimulating factor 3 or G-CSF granulocyte colony-stimulating factor)

Controls cellular proliferation and differentiation of granulocytes[60]

Increased with illness severity[3] Decreased[30]
KITLG (KIT ligand or SCF stem cell factor or MCGF mast cell growth factor or SLF steel factor)

Regulates cell survival and proliferation

Increased with illness severity[3]

Increased in early illness[2]

Decreased[30]

Decreased in later illness[2]

Transforming Growth Factors Regulation of immune cells
TGF-α (Transforming growth factor alpha)

Regulates cellular proliferation and differentiation

Increased with illness severity[3]
TGF‐β (Transforming growth factor beta)

Regulates cellular proliferation and differentiation, and inflammatory processes

Increased[3][61][62]

Increased TGF-β1[53][63]

Increased at rest, but not post-exercise[64]

Activin Part of the TGF-β protein superfamily. Involved in the control of inflammation and muscle mass[65] Increased Activin B[66][65] Decreased Activin B[67]
GDF15 (Growth differentiation factor 15)

Part of the TGF-β protein superfamily. Highly elevated GDF15 has been linked to mitochondrial disorders and skeletal muscle fatigue[68]

Increased[68]
Adipokines
Leptin Dual role, acting as both a hormone and cytokine. Critical in metabolic function. Helps regulate innate and adaptive immune response[69] Increased[2]

Increased with illness severity[3][70]

Resistin (Also known as ADSF adipose tissue-specific secretory factor or XCP1 C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein) Decreased[3]
Neurotrophins
NGF (Nerve growth factor)

Regulates neuronal cell function and immune cell activity[71]

Increased with illness severity[3][72]
Other Growth Factors
PDGFB (Platelet derived growth factor subunit B)

Regulates cellular proliferation and differentiation, and embryonic development[73]

Increased in later illness[2] Decreased PDGF-BB[30]

Decreased in early illness[2]

FGF2 (Fibroblast growth factor 2 or bFGF basic fibroblast growth factor or FGF-β)

Regulates cellular proliferation and differentiation

Decreased[30]
VEGFA (Vascular endothelial growth factor A)

Regulates cellular proliferation and differentiation of vascular endothelial cells[74]

Decreased[30]

Decreased in later illness[4]

Cytokines and Chemokines[edit | edit source]

Chemokines are cytokines that induce chemotaxis. Chemotaxis is the orchestrated movement of cells towards a specific location flagged by a chemical messenger. Unlike cytokines, chemokines have just one major role: to direct leukocytes toward pathogens, or to areas of injured/diseased tissue.

Notable studies[edit | edit source]

Learn More[edit | edit source]

See also[edit | edit source]

References[edit | edit source]

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