Cytokine
Encyclopedia
Cytokines are small cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

-signaling protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 molecules that are secreted by the glial cells of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...

 and by numerous cells of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 and are a category of signaling molecules used extensively in intercellular communication. Cytokines can be classified as proteins, peptides, or glycoproteins; the term "cytokine" encompasses a large and diverse family of regulators produced throughout the body
Body
With regard to living things, a body is the physical body of an individual. "Body" often is used in connection with appearance, health issues and death...

 by cells of diverse embryological origin.

The term "cytokine" has been used to refer to the immunomodulating
Immunomodulator
An immunomodulator, also known as an immunotherapy is a substance which has an effect on the immune system.- Immunosuppressants :Inhibits immune response in organ transplantation and autoimmune diseases.- Immunostimulants :...

 agents, such as interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...

s and interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

s. Biochemists disagree as to which molecules should be termed cytokines and which hormones. As we learn more about each, anatomic and structural distinctions between the two are fading. Classic protein hormones circulate in nanomolar (10) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10) concentrations that can increase up to 1,000-fold 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 macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s (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 glands (e.g., the pancreas). As of 2008, the current terminology refers to cytokines as immunomodulating agents. However, more research is needed in this area of defining cytokines and hormones.

Part of the difficulty with distinguishing cytokines from hormones is that some of the immunomodulating effects of cytokines are systemic rather than local. For instance, to use hormone terminology, the action of cytokines may be autocrine or paracrine in chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

 and endocrine as a pyrogen. Further, as molecules, cytokines are not limited to their immunomodulatory role. For instance, cytokines are also involved in several developmental processes during embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...

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
Leukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...

 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)

Effects

Each cytokine has a matching cell-surface receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

. Subsequent cascades
Biochemical cascade
A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...

 of intracellular signalling then alter cell functions. This may include the upregulation and/or downregulation of several genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...

 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
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

.

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
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.

Said et al. showed that inflammatory cytokines cause an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1
Programmed cell death 1
Programmed cell death protein 1 is a protein that in humans is encoded by the PDCD1 gene. PDCD1 has also been designated as CD279 ....

 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.

Nomenclature

Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed function, cell of secretion, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism
Pleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...

, such distinctions, allowing for exceptions, are obsolete.
  • The term interleukin was initially used by researchers for those cytokines whose presumed targets are principally leukocytes
    White blood cell
    White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...

    . It is now used largely for designation of newer cytokine molecules discovered every day and bears little relation to their presumed function. The vast majority of these are produced by T-helper cells.
  • The term chemokine refers to a specific class of cytokines that mediates chemoattraction (chemotaxis
    Chemotaxis
    Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

    ) between cells.

Structural

Structural homology 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
    Helix bundle
    A helix bundle is a small protein fold composed of several alpha helices that are usually nearly parallel or antiparallel to each other.-Three-helix bundles:Three-helix bundles are among the smallest and fastest known cooperatively folding structural domains...

     family - Member cytokines have three-dimensional structures with four bundles of α-helices
    Alpha helix
    A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...

    . This family, in turn, is divided into three sub-families:
    1. the IL-2
      Interleukin 2
      Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...

       subfamily
    2. the interferon (IFN)
      Interferon
      Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

       subfamily
    3. the IL-10
      Interleukin 10
      Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....

       subfamily.
    • The first of these three subfamilies is the largest. It contains several non-immunological cytokines including erythropoietin
      Erythropoietin
      Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...

       (EPO) and thrombopoietin
      Thrombopoietin
      Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....

       (TPO). Also, four α-helix bundle cytokines can be grouped into long-chain and short-chain cytokines.
  • the IL-1 family, which primarily includes IL-1 and IL-18
    Interleukin
    Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...

  • the IL-17
    Interleukin 17
    Interleukin-17 is the founding member of a group of cytokines called the IL-17 family. IL-17A, was originally identified as a transcript from a rodent T-cell hybridoma by Rouvier et al. in 1993...

     family, which has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that cause cytotoxic effects

Functional

A classification that proves more useful in clinical and experimental practice divides immunological cytokines into those that enhance cellular immune responses, type 1 (IFN-γ, TGF-β, etc.), and type 2 (IL-4
Interleukin 4
Interleukin-4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent...

, IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....

, IL-13
Interleukin 13
Interleukin 13 is a protein that in humans is encoded by the IL13 gene. IL-13 is cytokine secreted by many cell types, but especially T helper type 2 cells, that is a mediator of allergic inflammation and disease.-Functions:...

, etc.), which favor antibody responses.

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
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...

 of autoimmune disorders.

Several inflammatory cytokines are induced by oxidant stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

. The fact that cytokines themselves trigger the release of other cytokines and also lead to increased oxidant stress makes them important in chronic inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

.

Cytokine 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 pleiomorphism 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
    Immunoglobulin superfamily
    The immunoglobulin superfamily is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins ; they all possess a...

    , which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology
    Homology (biology)
    Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...

     with immunoglobulins (antibodies
    Antibody
    An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

    ), cell adhesion molecule
    Cell adhesion molecule
    Cell Adhesion Molecules are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix in the process called cell adhesion....

    s, and even some cytokines. Examples: IL-1 receptor types.
  • Haemopoietic Growth Factor
    Growth factor
    A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

     (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
    Severe combined immunodeficiency
    Severe combined immunodeficiency , is a genetic disorder in which both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency...

     (X-SCID
    X-SCID
    X-linked severe combined immunodeficiency is an immunodeficiency disorder that affects lymphocytes. It is a recessive trait stemming from a defective version of the gene responsible for the functionality of the Interleukin 2 receptor ....

    ).
  • Interferon
    Interferon
    Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

     (type 2) family, whose members are receptors for IFN β and γ.
  • Tumor necrosis factors
    Tumor necrosis factors
    Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...

     (TNF) (type 3) family, whose members share a cysteine
    Cysteine
    Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

    -rich common extracellular binding domain, and includes several other non-cytokine ligands like CD40, CD27
    CD27
    CD27 is a tumor necrosis factor receptor.-Interactions:CD27 has been shown to interact with SIVA1, TRAF2 and TRAF3.-External links:...

     and CD30
    CD30
    CD30, also known as TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker.This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the...

    , besides the ligands on which the family is named (TNF).
  • 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
    HIV
    Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

     (CXCR4
    CXCR4
    C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...

     and CCR5
    CCR5
    C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...

    ), also belong to this family .

Disease

Adverse effects of cytokines have been linked to many disease states and conditions ranging from major depression and Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 with levels either being elevated or changed. Oversecretion of cytokines can trigger a dangerous syndrome known as a cytokine storm
Cytokine storm
A cytokine storm, or hypercytokinemia is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells, with highly elevated levels of various cytokines.-Symptoms:...

; this may have been the cause of severe adverse events during a clinical trial of TGN1412
TGN1412
TGN1412 is the working name of an immunomodulatory drug which was withdrawn from development after inducing severe inflammatory reactions in the first human subjects to receive the drug....

.

Plasma levels

Plasma levels of various cytokines may give information on the presence, or even predictive value of inflammatory processes involved in autoimmune diseases such as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

, as well as immunomodulatory effects of foods or drugs. In addition, elevated levels of IL-7, an important cytokine involved in T cell homeostasis, have been detected in the plasma of HIV-infected patients
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

.

Cysteine-knot cytokines

Members of the transforming growth factor beta superfamily
Transforming growth factor beta superfamily
The transforming growth factor beta superfamily is a large family of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983....

 belong to this group, including TGF-β1
TGF beta 1
Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis...

, TGF-β2
TGF beta 2
Transforming growth factor-beta 2 is a secreted protein known as a cytokine that performs many cellular functions and has a vital role during embryonic development . It is an extracellular glycosylated protein...

 and TGF-β3
TGF beta 3
Transforming growth factor beta 3 is a type of protein, known as a cytokine, which is involved in cell differentiation, embryogenesis and development...

.

See also

  • Active Hexose Correlated Compound
    Active Hexose Correlated Compound
    Active Hexose Correlated Compound is an alpha-glucan rich nutritional supplement produced from the mycelia of shiitake of the basidiomycete family of mushrooms, and is not an approved drug. AHCC was originally designed to lower high-blood pressure...

  • Adipokine
    Adipokine
    The adipokines or adipocytokines are cytokines secreted by adipose tissue.Members include:* chemerin* interleukin-6...

    s
  • Apoptosis
    Apoptosis
    Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

  • Cytokine secretion assay
    Secretion assay
    Secretion assay is a process used in cell biology to identify cells that are secreting a particular protein . It was first developed by Manz et al. in 1995....

  • Cytokine storm
    Cytokine storm
    A cytokine storm, or hypercytokinemia is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells, with highly elevated levels of various cytokines.-Symptoms:...

  • ELISA
    ELISA
    Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...

     assays
  • ELISPOT
    ELISPOT
    The Enzyme-linked immunosorbent spot assay is a common method for monitoring immune responses in humans and animals. It was developed by Cecil Czerkinsky in 1983....

     assays
  • FluoroSpot
    FluoroSpot
    The FluoroSpot assay is a modification of the ELISPOT assay. ELISPOT usually measures the cellular secretion of one cytokine in each well by the use of an enzyme-labeled anti-cytokine antibody. FluoroSpot measures the secretion of several cytokines in each well by the use of fluorescent...

     assays
  • Granulocyte-colony stimulating factor
  • Signal transduction
    Signal transduction
    Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

  • Interleukin-7
  • TSLP
    TSLP
    Thymic stromal lymphopoietin is a protein belonging to the cytokine family. It is known to play an important role in the maturation of T cell populations through activation of antigen presenting cells....


External links

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