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 autoc ...
) that is secreted from immune cells like
helper T cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...
s (T
h) and
macrophages, and certain other cell types that promote
inflammation. They include
interleukin-1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on t ...
(IL-1),
IL-6,
IL-12, and
IL-18,
tumor necrosis factor alpha (TNF-α),
interferon gamma
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
(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 the ...
. 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 no ...
and
cancer. 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
Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. I ...
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
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
.
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 autoc ...
(a signaling molecule) that is secreted from immune cells and certain other cell types that promotes
inflammation. Inflammatory cytokines are predominantly produced by
T helper cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
s (T
h) and
macrophages and involved in the
upregulation
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...
of inflammatory reactions.
Therapies to treat inflammatory diseases include
monoclonal antibodies that either neutralize inflammatory cytokines or their
receptors
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
.
Inflammatory cytokines include
interleukin-1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on t ...
(IL-1),
IL-12, and
IL-18,
tumor necrosis factor alpha (TNF-α),
interferon gamma
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
(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 the ...
. Some inflammatory cytokines have additional roles such as acting as
growth factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
.
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
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...
. TNF-α is often involved in different signaling pathways to regulate
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
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 no ...
and
cancer. 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,
inflammation, tissue destruction, and in some cases, even
shock
Shock may refer to:
Common uses Collective noun
*Shock, a historic commercial term for a group of 60, see English numerals#Special names
* Stook, or shock of grain, stacked sheaves
Healthcare
* Shock (circulatory), circulatory medical emerge ...
and
death.
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
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
from the
nephron
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure c ...
. As a result, there is a change in the activity of the
potassium ion
Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosph ...
(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
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer me ...
. 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
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
.
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
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule dona ...
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
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
. 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. 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
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
, possibly due to the primary deficiency in the
cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wi ...
(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 no ...
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
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 adipogenesis. I ...
generate TNF-α and other
interleukins
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
. 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 e ...
serve as remote regulators such as
hormones
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required fo ...
. Studies have shown that TNF-α and IL-6 concentrations are elevated in
obesity.
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 adipogenesis. ...
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
Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
matrix degradation and
bone resorption
Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood.
The osteoclasts are multi-nucle ...
in
osteoarthritis. Animal studies indicate that inflammatory cytokines may stimulate
chondrocytes
Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
to release cartilage-degrading
protease in osteoarthritis. This finding does not, however, necessarily translate to ''
Homo sapiens'', 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 well ...
,
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
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
,
IL-6, and
IL-10.
Estrogen 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
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
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