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 produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

) 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 considere ...

s (T_h) and

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s, and certain other cell types that promote

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. 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 (IFNG or 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. ...

(IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions. Excessive chronic production of inflammatory cytokines contribute to

inflammatory disease Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants. The five cardinal signs are heat, pain, redness, swelling, and Functio laesa, loss of funct ...

s, that have been linked to different diseases, such as

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

and

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. 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 (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...

and

exercise Exercise or workout is physical activity that enhances or maintains fitness and overall health. It is performed for various reasons, including weight loss or maintenance, to aid growth and improve strength, develop muscles and the cardio ...

also play a role in the amount of inflammation from the release of proinflammatory cytokines. Therapies to treat inflammatory diseases include

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Mon ...

that either neutralize inflammatory cytokines or their receptors.

Definition

An inflammatory cytokine is a type of

(a signaling molecule) that is secreted from immune cells and certain other cell types that promotes

. 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

s and involved in the

upregulation In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as R ...

of inflammatory reactions. Therapies to treat inflammatory diseases include

that either neutralize inflammatory cytokines or their receptors. Inflammatory cytokines include

(IL-1), IL-12, and IL-18, tumor necrosis factor alpha (TNF-α),

(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. 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 (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...

. TNF-α is often involved in different signaling pathways to regulate

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

in the cells. Excessive chronic production of inflammatory cytokines contribute to

s. that have been linked to different diseases, such as

and

. 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 or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

, tissue destruction, and in some cases, even shock and

death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...

. 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 structu ...

. As a result, there is a change in the activity of the

potassium ion Potassium is a chemical element; it has symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to form flaky white pot ...

(K+) channels that changes the transepithelial transport of solutes and water in the kidney. The kidney

proximal tubule The proximal tubule is the segment of the nephron in kidneys which begins from the renal (tubular) pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s ...

cells produce proinflammatory cytokines in response to

lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...

. 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 the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...

Graft-vs-host disease

Graft-versus-host disease Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which rema ...

(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 cla ...

protein required for signaling in multiple cytokines. When these

kinases In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...

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 biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

. 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 T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

, T_H1, T_H2, or T_H17 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 genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...

. 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 common 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 wh ...

, 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 lin ...

(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, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

induces a dysfunctional endothelium, which recruits immune cells that form lesions. Proinflammatory mediators cause inflammation after

ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...

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 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 (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

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 or tissues by complex biological processes to regulate physiology and behavior. Hormones a ...

. Studies have shown that TNF-α and IL-6 concentrations are elevated in

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. Obesity leaves an excess of nutrients for the body, thereby causing

adipocyte Adipocytes, also known as lipocytes and fat cells, are the cell (biology), 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 ...

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. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...

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-nuclea ...

osteoarthritis Osteoarthritis is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone. A form of arthritis, it is believed to be the fourth leading cause of disability in the world, affect ...

. Animal studies indicate that inflammatory cytokines may stimulate

chondrocytes Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...

to release cartilage-degrading

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

in osteoarthritis. This finding does not, however, necessarily translate to ''

Homo sapiens Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

'', as osteoarthritis in humans is considered to be more complex than any animal model.

Fatigue

Cytokines have key roles in inflammation, which is seen as a causal mechanism in

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

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, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...

, 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 (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

has been shown to promote healing by decreasing 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 agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...

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