An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...
) that is secreted from immune cells like
helper T cells (T
h) and
macrophages, and certain other cell types that promote
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
. They include
interleukin-1 (IL-1),
IL-6,
IL-12, and
IL-18,
tumor necrosis factor alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolo ...
(TNF-α),
interferon gamma (IFNγ), and
granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the
innate immune response
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is th ...
. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.
Excessive chronic production of inflammatory cytokines contribute to
inflammatory diseases, that have been linked to different diseases, such as
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually ...
and
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
. Dysregulation has also been linked to
depression and other neurological diseases. A balance between proinflammatory and anti-inflammatory cytokines is necessary to maintain health.
Aging and
exercise also play a role in the amount of inflammation from the release of proinflammatory cytokines.
Therapies to treat inflammatory diseases include
monoclonal antibodies that either neutralize inflammatory cytokines or their
receptors.
Definition
An inflammatory cytokine is a type of
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...
(a signaling molecule) that is secreted from immune cells and certain other cell types that promotes
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
. Inflammatory cytokines are predominantly produced by
T helper cells (T
h) and
macrophages and involved in the
upregulation of inflammatory reactions.
Therapies to treat inflammatory diseases include
monoclonal antibodies that either neutralize inflammatory cytokines or their
receptors.
Inflammatory cytokines include
interleukin-1 (IL-1),
IL-12, and
IL-18,
tumor necrosis factor alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolo ...
(TNF-α),
interferon gamma (IFNγ), and
granulocyte-macrophage colony stimulating factor (GM-CSF).
Function
Inflammatory cytokines play a role in initiating the inflammatory response and to regulate the host defence against pathogens mediating the
innate immune response
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is th ...
. Some inflammatory cytokines have additional roles such as acting as
growth factors.
Pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α also trigger pathological pain.
While IL-1β is released by monocytes and macrophages, it is also present in nociceptive DRG neurons. IL-6 plays a role in neuronal reaction to an injury. TNF-α is a well known proinflammatory cytokine present in neurons and the
glia. TNF-α is often involved in different signaling pathways to regulate
apoptosis in the cells.
Excessive chronic production of inflammatory cytokines contribute to
inflammatory diseases.
that have been linked to different diseases, such as
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually ...
and
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
. Dysregulation of proinflammatory cytokines have also been linked to
depression and other neurological diseases. A balance between proinflammatory and anti-inflammatory cytokines is necessary to maintain health. Aging and exercise also play a role in the amount of inflammation from the release of proinflammatory cytokines.
Negative impacts
Due to its proinflammatory action, a proinflammatory cytokine tends to make the disease itself or the symptoms correlated to a disease worse by causing
fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
,
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, tissue destruction, and in some cases, even
shock and
death
Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
.
Excessive amounts of proinflammatory cytokines have been shown to cause detrimental effects
In the kidney
A proinflammatory cytokine affects functions of transporters and
ion channels from the
nephron. As a result, there is a change in the activity of the
potassium ion (K+) channels that changes the transepithelial transport of solutes and water in the kidney. The kidney
proximal tubule cells produce proinflammatory cytokines in response to
lipopolysaccharide. Proinflammatory cytokines affect the renal K+ channels. IFNγ causes delayed suppression and acute stimulation of the 40 pS K+ channel. Also,
transforming growth factor beta 1 (TGF-β1) activates the calcium-activated potassium channel (
KCa3.1) which could be involved the detrimental effects of renal
fibrosis.
Graft-vs-host disease
Graft-versus-host disease (GvHD) targets
JAK 1 and
2, the human
tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cl ...
protein required for signaling in multiple cytokines. When these
kinases are activated, signal proteins of the signal transducer and activator of transcription
(STAT) protein family - which include transcription factors for target genes that serve proinflammatory roles - are
phosphorylated. The severity of GvHD is highly variable and is influenced by the amount of native cells present in the environment along with other regulatory
T cells,
TH1,
TH2, or
TH17 phenotypes. Both CD4
+ and CD8 IL-17 producing T cells have been shown to cause aTH1, causing tissue inflammation and resulting in severe GVHD.
In cystic fibrosis
A proinflammatory cytokine causes hyperinflammation, the leading cause of lung tissue destruction in
cystic fibrosis
Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. ...
. With such a strong inflammatory response and an elevated number of immune cells, lungs of cystic fibrosis patients cannot clear the bacteria and become more susceptible to infections. A high prevalence (40-70%) of patients with cystic fibrosis show signs of
asthma, possibly due to the primary deficiency in the
cystic fibrosis transmembrane conductance regulator (CFTR). CFTR-deficient T-helper cells create an inflammatory environment that has high concentrations of TNF-α, IL-8, and IL-13, which contributes to increased contractility of airway smooth muscle.
In cardiovascular disease
Atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually ...
induces a dysfunctional endothelium, which recruits immune cells that form lesions. Proinflammatory mediators cause inflammation after
ligands in the heart vasculature activate immune cells. Recent studies have shown the ability of exercise to control oxidative stress and inflammation in cardiovascular disease.
In adipose tissue metabolism and obesity
A proinflammatory cytokine may be present in
adipose tissues.
Adipocytes generate TNF-α and other
interleukins. Cytokines derived from
adipose tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...
serve as remote regulators such as
hormones. Studies have shown that TNF-α and IL-6 concentrations are elevated in
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
.
Obesity leaves an excess of nutrients for the body, thereby causing
adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesi ...
s to release more proinflammatory cytokines. Classically activated macrophages in the visceral fat accumulate in the fat tissues and continuously release proinflammatory cytokines, causing chronic inflammation in obese individuals.
In osteoarthritis
TNF-α, IL-1 and IL-6 have been found to play a pivotal role in
cartilage matrix degradation and
bone resorption in
osteoarthritis. Animal studies indicate that inflammatory cytokines may stimulate
chondrocytes to release cartilage-degrading
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the form ...
in osteoarthritis. This finding does not, however, necessarily translate to ''
Homo sapiens
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
'', as osteoarthritis in humans is considered to be more complex than any animal model.
Clinical implications
Reducing the biological activity of proinflammatory cytokine can reduce the brunt of attack from diseases.
Blocking IL-1 or TNF-α has been highly successful in helping patients with rheumatoid arthritis,
inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine and large intestine, as wel ...
,
or graft-vs-host disease (GvHD).
However, the strategy has not yet been successful in humans with sepsis.
Therapeutic effects of acupuncture may be related to the body's ability to suppress a range of proinflammatory cytokines such as
tumor necrosis factor alpha (TNF-α),
IL-1B,
IL-6, and
IL-10.
Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...
has been shown to promote healing by decrease the production of various proinflammatory cytokines like IL-6, TNF-α, and macrophage migration inhibitory factor (
MIF). Increased MIF levels are often found at the site of chronic non-healing ulcers, with those levels dropping significantly with successful healing. A 2005 review of current experimental data shows that "estrogen regulates healing almost exclusively via MIF down-regulation and identifies novel MIF-regulated gene targets and clusters associated with aberrant healing." By down-regulating MIF, estrogen can promote healing, as correlated by clinical studies on aging skin and skin wounds. Unfortunately, estrogen-therapy has known
carcinogenic effects as mentioned by the American Cancer Society (increased incidences of breast cancer in women who undergo
HRT). However, scientists could make important discoveries in the future by studying "downstream effects on genes/factors that mediate the effects of estrogen on healing."
Histone deacetylate inhibitors (
HDACi) can suppress proinflammatory cytokine production and reduce GvHD.
Some research also suggest an immunoregulatory effect of vitamin D, which has been shown to reduce the secretion of specific inflammatory cytokines.
References
{{Cytokine receptor modulators
Cytokines