Cytokines ()[ ] are a broad and loose category of small (~5–25 kDa
Cytokines are usually too large to cross Cell membrane and enter cells. They typically function by interacting with specific cytokine receptors on the surface of target cells. Cytokines include , , , , and tumour necrosis factors, but generally not or (despite some overlap in the terminology).
Cytokines are especially important in the immune system, including in Immune response and inflammation. Cytokines modulate the balance between humoral immunity 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 (autocrine signaling), nearby cells (paracrine signaling), and other cells throughout the body (Endocrine system signaling).
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
,
, and
, based on their presumed cell of secretion, function, or target of action. Because cytokines are characterised by considerable redundancy and
Pleiotropy, 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 (leukocytes). 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 .
-
Lymphokines: produced by lymphocytes
-
Monokines: produced exclusively by monocytes
-
Interferons: involved in antiviral responses
-
Colony stimulating factors: support the growth of cells in semisolid media
-
Chemokines: mediate chemoattraction (chemotaxis) 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-Helix bundle family (): member cytokines have three-dimensional structures with a bundle of four alpha helix. This family, in turn, is divided into three sub-families:
-
the IL-2 subfamily. This is the largest family. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO).
-
the interferon subfamily.
-
the IL-10 subfamily.
-
The IL-1 family, which primarily includes IL-1 and interleukin.
-
The cysteine knot cytokines () include members of the transforming growth factor beta superfamily, including TGF-β1, TGF-β2 and TGF-β3.
-
The IL-17 family, which has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that have cytotoxic effects.
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 (TNFα, IFN-γ, etc.), and those that enhance
antibody responses, type 2 (TGF-β, IL-4, IL-10, IL-13, etc.).
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
Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury.
Difference from hormones
Classic
circulate in
aqueous solution in nanomolar (10 M) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10 M) concentrations that can increase up to 1,000 times during
injury 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
(many near the interface with the external environment) are potent producers of IL-1, IL-6, and TNF-α.
In contrast, classic hormones, such as
insulin, are secreted from discrete
such as the
pancreas.
The current terminology refers to cytokines as
Immunotherapy.
A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulation effects of cytokines are systemic ( i.e., affecting the whole organism) 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.
-
Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology with immunoglobulins (antibody), cell adhesion molecules, and even some cytokines. Examples: IL-1 receptor types.
-
Hemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency (X-SCID).
-
Interferon (type 2) family, whose members are receptors for IFN β and γ.
-
Tumor necrosis factors (TNF) (type 3) family, whose members share a cysteine-rich common extracellular binding domain, and includes several other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands on which the family is named.
-
Seven transmembrane helix family, the ubiquitous receptor type of the animal kingdom. All G protein-coupled receptors (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for HIV (CD4 and CCR5), also belong to this family.
-
Interleukin-17 receptor (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.
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
enzyme inhibitor. 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
antibody 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[James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. .]
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.
[Saito explains "much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems."(15)][Chen explains the regulatory activity of LIF in human and murine embryos: "In conclusion, human preimplantation embryos express LIF and LIF-R mRNA. The expression of these transcripts indicates that preimplantation embryos may be responsive to LIF originating either from the surrounding environment or from the embryos themselves and exerting its function in a paracrine or autocrine manner." (719)] 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
In March 2025, researchers in Saudi Arabia found that those who received mRNA COVID-19 vaccines showed elevated cytokine levels one year after the vaccination, and the immune responses differed between gender and age groups. The vaccination resulted in significant increases in inflammatory markers:
interferon gamma (INF gamma, p=0.005), tumor necrosis factor alpha (TNF alpha, p<0.001), interleukin-6 (IL6, p=0.003), monocyte chemoattractants (MCP1, p=0.03, MCP3, p=0.001) and so on. Bigger changes in IL6, IL4 and TNF alpha were observed in men than in women, and significant changes in epidermal growth factor (EGF), IL6, MCP1, and TNF alpha were seen in adults compared to adolescents. The researchers speculated that the elevation may be attributed to the persistent production of spike protein and highly inflammatory nature of mRNA-nanoparticles.
[
]
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.
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 (
Tregs) 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 (Foxp3) as a transcription factor is an essential molecular marker of
Treg cells. Foxp3 polymorphism (rs3761548) 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.
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:
-
Bone morphogenetic protein (BMP), used to treat bone-related conditions
-
Erythropoietin (EPO), used to treat anemia
-
Granulocyte colony-stimulating factor (G-CSF), used to treat neutropenia in cancer patients
-
Granulocyte macrophage colony-stimulating factor (GM-CSF), used to treat neutropenia and fungal infections in cancer patients
-
Interferon alfa, used to treat hepatitis C and multiple sclerosis
-
Interferon beta, used to treat multiple sclerosis
-
Interleukin 2 (IL-2), used to treat cancer.
-
Interleukin 11 (IL-11), used to treat thrombocytopenia in cancer patients.
-
Interferon gamma is used to treat chronic granulomatous disease
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 (the sole member of the interferon type II class) was described in 1965; this was the first identified
lymphocyte-derived mediator.
Macrophage migration inhibitory factor (MIF) 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".
See also
Notes
External links
target="_blank" rel="nofollow"> Cytokine Gene Summary, Ontology, Pathways and More: Immunology Database and Analysis Portal (ImmPort)
