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 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 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:

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.
the interferon subfamily.
the IL-10 subfamily.

The IL-1 family, which primarily includes IL-1 and IL-18.
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, 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.

Immunoglobulin superfamily, which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology with immunoglobulins, cell adhesion molecules, and even some cytokines. Examples: IL-1 receptor types.
Hemopoietic Growth Factor family, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency.
Interferon family, whose members are receptors for IFN β and γ.
Tumor necrosis factors 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 belong to this family. Chemokine receptors, two of which act as binding proteins for HIV, also belong to this family.
Interleukin-17 receptor 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 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.