Cytokine


Cytokines are a broad and loose category of small proteins important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells, as well as endothelial cells, fibroblasts, and various types of connective tissue cells. A single cytokine may be produced by more than one type of cell.
Cytokines are usually too large to cross cell membranes and enter cells. They typically function by interacting with specific cytokine receptors on the surface of target cells. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors, but generally not hormones or growth factors.
Cytokines are especially important in the immune system, including in immune responses and inflammation. Cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways. Cytokines are generally released in lower concentrations than hormones. Immune cytokines released by one cell can send signals to the same cell, nearby cells, and other cells throughout the body.

Terminology and nomenclature

Terminology

The word comes from the ancient Greek language: cyto, from Greek κύτος, kytos, 'cavity, cell' + kines, from Greek κίνησις, kinēsis, 'movement'.

Nomenclature

Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed cell of secretion, function, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism, such distinctions, allowing for exceptions, are obsolete.
  • The term interleukin was initially used by researchers for those cytokines whose presumed targets are principally white blood cells. It is now used largely for designation of newer cytokine molecules and bears little relation to their presumed function. The vast majority of these are produced by T-helper cells.Lymphokines: produced by lymphocytesMonokines: produced exclusively by monocytesInterferons: involved in antiviral responsesColony stimulating factors: support the growth of cells in semisolid mediaChemokines: mediate chemoattraction between cells.

Classification

Structural

Structural homogeneity has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:
  • The four-α-helix bundle family : member cytokines have three-dimensional structures with a bundle of four α-helices. This family, in turn, is divided into three sub-families:
  1. the IL-2 subfamily. This is the largest family. It contains several non-immunological cytokines including erythropoietin and thrombopoietin. They can be grouped into long-chain and short-chain cytokines by topology. Some members share the common gamma chain as part of their receptor.
  2. the interferon (IFN) subfamily.
  3. the IL-10 subfamily.

Functional

A classification that proves more useful in clinical and experimental practice outside of structural biology divides immunological cytokines into those that enhance cellular immune responses, type 1, and those that enhance antibody responses, type 2.
A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Dysregulation of this tendency is under intensive study for its possible role in the pathogenesis of autoimmune disorders.
Several inflammatory cytokines are induced by oxidative stress.
The fact that cytokines themselves trigger the release of other cytokines and lead to increased oxidative stress makes them important in chronic inflammation, as well as other immunoresponses, such as fever and acute phase proteins of the liver.
Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury. There are both pro-inflammatory and anti-inflammatory cytokines that regulate this pathway.

Difference from hormones

Classic hormones circulate in aqueous solution in nanomolar concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines circulate in picomolar concentrations that can increase up to 1,000 times during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages are potent producers of IL-1, IL-6, and TNF. In contrast, classic hormones, such as insulin, are secreted from discrete glands such as the pancreas. The current terminology refers to cytokines as immunomodulating agents.
A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulating effects of cytokines are systemic rather than local. For instance, to accurately utilize hormone terminology, cytokines may be autocrine or paracrine in nature, and chemotaxis, chemokinesis and endocrine as a pyrogen. Essentially, cytokines are not limited to their immunomodulatory status as molecules.

Receptors

In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.
A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.

Cellular effects

Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signaling then alter cell functions. This may include the upregulation and/or downregulation of several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition. The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type. Cytokines are characterized by considerable redundancy, in that many cytokines appear to share similar functions. It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.
It has been shown that inflammatory cytokines cause an IL-10-dependent inhibition of T-cell expansion and function by up-regulating PD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L. Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Occasionally such reactions are seen with more widespread papular eruptions.

Functions in health and disease

Infections and other immune responses

Cytokines are crucial for fighting off infections and in other immune responses. However, they can become dysregulated and pathological in inflammation, trauma, sepsis, and hemorrhagic stroke.

Embryo development

Cytokines are involved in several developmental processes during embryonic development. Cytokines are released from the blastocyst, and are also expressed in the endometrium, and have critical roles in the stages of zona hatching, and implantation.

Ageing

Dysregulated cytokine secretion in the aged population can lead to inflammaging, and render these individuals more vulnerable to age-related diseases like neurodegenerative diseases and type 2 diabetes.

Narcolepsy and fatigue

A 2024 study found a positive correlation between plasma interleukin IL-2 and fatigue in patients with type 1 narcolepsy.

COVID-19

Autoantibodies against cytokines also plays a role in health and disease. In 2020 neutralizing autoantibodies against type I interferons were reported in 10.2% of patients with life-threatening COVID-19.
In a subsequent follow-up study, researchers investigated that the prevalence of autoantibodies against type I interferons increases with age. Only 0.17% of individuals under 70 years of age tested positive for these autoantibodies, compared with 4.2% among those aged 80 to 85 years. Furthermore, autoantibodies against IFN-α/ω were detected in approximately 20% of patients over 80 years old with critical COVID-19.

ME/CFS

A 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS.

Adverse effects

Adverse effects of cytokines have been linked to many disease states and conditions including schizophrenia, major depression, Alzheimer's disease, and cancer.

Tumors

T regulatory cells and related-cytokines are effectively engaged in the process of tumor immune escape and functionally inhibit immune response against the tumor. Forkhead box protein 3 as a transcription factor is an essential molecular marker of Treg cells. Foxp3 polymorphism might be involved in cancer progression like gastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β.
Normal tissue integrity is preserved by feedback interactions between diverse cell types mediated by adhesion molecules and secreted cytokines; disruption of normal feedback mechanisms in cancer threatens tissue integrity.

Cytokine storms

Over-secretion of cytokines can trigger a dangerous cytokine storm syndrome.
Cytokine storms may have been the cause of severe adverse events during a clinical trial of TGN1412.
Cytokine storms are also suspected to have been the main cause of death in the 1918 "Spanish Flu" pandemic. Deaths were weighted more heavily towards people with healthy immune systems, because of their ability to produce stronger immune responses, with dramatic increases in cytokine levels.
Another example of cytokine storm is seen in acute pancreatitis. Cytokines are integral and implicated in all angles of the cascade, resulting in the systemic inflammatory response syndrome and multi-organ failure associated with this intra-abdominal catastrophe.
In the COVID-19 pandemic, some deaths from COVID-19 have been attributable to cytokine release storms. Data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation in COVID-19 infections.
Prenatal SARS-COV-2 infection in pregnant women is linked to developmental delays with high level of interferon-gamma in cord blood correlated with cognitive delays, while interleukin-6, IL-8, IL-17, and IL-1β were associated with motor delays.

Medical use as drugs

Some cytokines have been developed into protein therapeutics using recombinant DNA technology. Recombinant cytokines being used as drugs as of 2014 include:

History of discovery

Interferon-alpha, an interferon type I, was identified in 1957 as a protein that interfered with viral replication. The activity of interferon-gamma was described in 1965; this was the first identified lymphocyte-derived mediator. Macrophage migration inhibitory factor was identified simultaneously in 1966 by John David and Barry Bloom.
In 1969, Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines". In 1974, pathologist Stanley Cohen, M.D. published an article describing the production of MIF in virus-infected allantoic membrane and kidney cells, showing its production is not limited to immune cells. This led to his proposal of the term cytokine. In 1993, Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.