Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). There are both pro-inflammatory cytokines and anti-inflammatory cytokines.

Types of Cytokines Participating in Immune Response

Cytokines are small cell-signaling protein molecules secreted by numerous cells.

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 characterized 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 (leukocytes). It is now used largely for the 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 (chemotaxis) between cells.

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 (InterPro: IPR009079): 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 (EPO) and thrombopoietin (TPO).[rx] They can be grouped into long-chain and short-chain cytokines by topology.[rx] Some members share the common gamma chain as part of their receptor.[rx]
    2. the interferon (IFN) subfamily.
    3. the IL-10 subfamily.
  • The IL-1 family, which primarily includes IL-1 and IL-18.
  • The cysteine knot cytokines (IPR029034) 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 the proliferation of T-cells that cause 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.[15][16] The fact that cytokines themselves trigger the release of other cytokines [17][18][19] and also lead to increased oxidative stress makes them important in chronic inflammation, as well as other immune responses, such as fever and acute-phase proteins of the liver (IL-1,6,12, IFN-a). Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury.[rx] There are both pro-inflammatory and anti-inflammatory cytokines that regulate this pathway.

Key Points

Cytokines are immune system regulatory agents that work at both systemic and local levels. Cytokines are also involved in several developmental processes during embryogenesis.

Each cytokine has a matching cell-surface receptor. Upon binding, intracellular signaling and gene expression regulations are altered, leading to the production of other cytokines, surface receptors, or feedback inhibition.

Interleukins principally target leukocytes. They include common inflammatory and anti-inflammatory mediators and lymphokines.

Chemokines mediate chemoattraction (chemotaxis) between cells.

Interferons have an antiviral function and can act as pyrogen.

Tumor necrosis factor causes long-lasting inflammatory effects and fever during systemic immune responses. It stimulates the acute phase reaction in the liver and is responsible for much of the immune system-caused damage in severe infections.

Key Terms

  • chemokine: Any of various cytokines produced during inflammation that organize the leukocytes by providing a stimulus for chemotaxis.
  • IL-10: Also known as human cytokine synthesis inhibitory factor (CSIF), an anti-inflammatory cytokine.
  • cytokine: Any of various small regulatory proteins or glycoproteins that regulate the cells of the immune system.

Cytokines are small cell-signaling protein molecules secreted by numerous cells and used extensively in intercellular communication. Cytokines can be classified as proteins, peptides, or glycoproteins. They provide the signaling pathways that orchestrate the complex immune responses of the human body. Cytokines are similar to hormones, which are also chemical messengers, but hormones have considerably more variation in molecular structure and are involved more in tissue signaling than cellular signaling.

Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signalling then alter cell functions. This may include the upregulation (increased expression) and/or downregulation (decreased expression) 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 effects by feedback inhibition.

Interleukins

Interleukins are a class of cytokines primarily expressed by leukocytes. They are glycoproteins involved in the signaling of many types of immune system functions. There are 17 different families of interleukins. Some of the more important ones include inflammatory mediators such as IL-1, IL-4, and IL-6, the potent anti-inflammatory IL-10, and other interleukins involved with T and B cell signaling following antigen presentation. Many interleukins are also considered lymphokines, interleukins released by helper T cells to organize immune responses.

Interferons

Interferons are protein cytokines that have antiviral functions. They can activate macrophages and natural killer (NK) cells to attack and lyse virus-infected cells. One common interferon is IFN-gamma, a pyrogen involved in inflammatory response and macrophage and NK cell activation. IFN-gamma is produced by T cells (both CD4 and CD8) and NK cells.

Chemokines

Chemokines are protein cytokines that are mainly involved in facilitating chemotaxis (chemical-stimulated movement) in immune cells. Leukocytes travel along chemotactic gradients that guide them to sites of injury, infection, or inflammation. By definition, inflammatory mediators in other classes of cytokines are also considered chemokines. This category also includes cytokines that are only involved in leukocyte migration, such as CCL2 which causes monocyte chemotaxis and stimulates its differentiation into macrophages inside of tissues.

Tumor Necrosis Factor

Tumor necrosis factors (TNF) are cytokines that induce apoptosis in abnormal cells such as tumor cells. It is a protein released by NK cells, macrophages, and helper T cells, typically in systemic immune responses. TNF-alpha is the most notable example. This long-lasting inflammatory mediator and pyrogen can cause fever and inflammation for up to 24 hours. It also stimulates acute phase reaction in the liver, a component of systemic immune system activation where the liver makes proteins involved in immune system response such as complement proteins. TNF-alpha is released in very high amounts in response to lipopolysaccharide  (infection with gram-negative bacteria), which facilitates much of the self-destructive immune response in septic shock. In these cases, TNF-alpha can cause organ failure from tissue hypoperfusion, caused by damage and blood clotting from an overactive immune response.

Selected cytokines and their primary activities

Cytokines Principal Source Primary Activity
GM-CSF Th cells Growth and differentiation of monocytes and dendritic cells
IL-1α
IL-β		 Macrophages and another antigen
presenting cells (APCs)		 Costimulation of APCs and T cells, inflammation and fever, acute phase response,
hematopoiesis
IL-2 Activated Th1 cells, NK cells With the proliferation of B cells and activated T cells, NK functions
IL-3 Activated T cells Growth of hematopoietic progenitor cells
IL-4 Activated T cells B cell proliferation, eosinophil and mast cell growth and function, IgE and class II MHC
the expression on B cells, inhibition of monokine production
IL-5 Th2 and mast cells Eosinophil growth and function
IL-6 Activated Th2 cells, APCs, other
somatic cells		 Acute-phase response, B cell proliferation, thrombopoiesis, synergistic with IL-1 and TNF on
T cells
IL-7 Thymic and marrow stromal cells T and B lymphopoiesis
IL-8 macrophages, somatic cells Chemoattractant for neutrophils and T cells
IL-9 T cells Hematopoietic and thymopoiesis effects
IL-10 Activated Th2 cells, CD8+ T and B
cells, macrophages		 Inhibits cytokine production, promotes B cell proliferation and antibody production,
suppresses cellular immunity, mast cell growth
IL-11 Atromal cells Synergistic hematopoietic and thrombopoiesis effects
IL-12 B cells, macrophages The proliferation of NK cells, IFN production, promotes cell-mediated immune functions
IL-13 Th2 cells IL-4-like activities
IL-18 Macrophages potent inducer of interferon-+ by T cells and NK cells
IFN-α
IFN-β		 Macrophages, neutrophils and
some somatic cells		 Antiviral effects, induction of class I MHC on all somatic cells, activation of NK cells and
macrophages
IFN-γ Activated Th1 and NK cells Induces of class I MHC on all somatic cells, induces class II MHC on APCs and somatic
cells, activates macrophages, neutrophils, NK cells, promotes cell-mediated immunity,
antiviral effects
MIP-1α Macrophages Chemotaxis
MIP-1β Lymphocytes Chemotaxis
TGF-β T cells, monocytes Chemotaxis, IL-1 synthesis, IgA synthesis, inhibit proliferation
TNF-α macrophages, mast cells, NK
cells, sensory neurons		 Cell death, inflammation, pain
TNF-β Th1 and Tc cells phagocytosis, NO production, cell death
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Basic mechanisms of cell communication.

Intracrine actions: intracellular action by regulation of intracellular events within the cytoplasm and/or nucleus.

Autocrine: action produced within the cell through surface cell receptors.

Intercrine: communication between cells. This type of cell interaction can be classified into:

  • Paracrine: signaling produced by soluble mediators through neighboring cells.
  • Matricrine: cytokines are immobilized in the extracellular matrix (ECM) by its binding to proteoglycans, and they are then stored in an inactive form. These cytokines will be released by the action of proteases such as Metalloproteinases (MMPs) by a mechanism know as Protease-triggered matricrine (PTM). Glycocalyx, which is made of glycoprotein carbohydrate motifs with proteoglycan on its surface, could play the same role.
  • Cytokine secretion by exchange of membrane fragments between cells through mechanisms such as trogocytosis, formation of tunneling nanotubes (TNTs), and release, secretion, and transportation of microvesicles (MVs)/Exosomes.
  • Juxtacrine: neighboring adjacent cells send signals through membrane-anchored mediators. The classic example is the action of the endothelium on the smooth muscle of the tunica media of certain vessels. Some cytokines have the ability to bind to extracellular matrix soluble proteoglycans or to proteoglycan-cell surfaces (for example, CD44, Glypicans, Syndecans, Betaglycan/TGFBR3, inter alia), where this mechanism serves as a reservoir, or as an enabler of these mediators to act on specific receptors in a juxtracrine manner.
  • Endocrine: this refers to the distal or systemic action which depends on secreted cytokine and its transportation within the blood.

Note that the autocrine, paracrine, juxtacrine, and endocrine actions are exerted by the binding to transducing signals (second messenger cascade) through specific cell surface receptors. Cytokines have limited biological half-lives and they act locally for the most part. Furthermore, they have overlapping actions characterized by a very broad range of functions, e.g., hematopoiesis, cell growth, and differentiation, angiogenesis, tissue remodeling, wound healing, effector immune cell activity, and life/death decisions. Moreover, cytokines with endocrine action circulate in picomolar concentrations, but under the influence of strong immune activation circumstances, they can surge up to 1,000-fold (cytokine mix).

In immunological jargon, terms such as interleukins (IL’s), monokines, lymphokines, haematopoietins, lymphopoietins, myelopoietins, leucopoietins, basophilopoietins, chalones, leucokines, macrophage-activator factors (MAF), macrophage inhibitor factors (MIF), histamine-releasing factors (HRF), endogenous pyrogens, tumor necrosis factors, and interferons were originally used to identify the cellular source, the target cell and/or their action-type. However, at present, it is clearly understood that these substances are produced by a multiplicity of cell populations, depending on whether the cell is in a physiological resting state, activated state, or in the pathological context of a specific scenario. The evolution of protein domain families is evident in the genesis and in the great diversity of different cytokines and cytokine-receptor families.

Chemokines (Chemoattractant cytokines) are a particular class of heat immune system cell communication mediators. They are a family of low molecular mass (8–14 kDa) proteins, most basic and structurally related, which exhibit a wide variety of immunological activities such as cell trafficking (–).

Fundamental classification

The nomenclature for genes and related diseases, which is used throughout this chapter is assigned by the Human Genome Organisation (HUGO), the Gene Nomenclature Committee (HGNC) by the National Human Genome Research Institute (NHGRI) (http://www.genenames.org/), and the Online Mendelian Inheritance in Man (OMIM) catalog, which is a registered trademark of Johns Hopkins. (http://omim.org/)

Archetypical cytokines signaling through classical-cytokine receptors

  1. Type I helical Cytokine families signaling through Class I cytokine receptors (CRF1 family or Hematopoietic family)
    1. IL-2 Family or Common gamma Chain Receptor Family: IL-2, IL-9, IL-15, IL-21, IL-4 subfamily (IL-4, IL-13), and IL7 subfamily (IL-7, TSLP)
    2. Common beta Chain Receptor Cytokine Family: IL-3, IL-5, and Colony Stimulating Factor 2/Granulocyte Monocyte-stimulating factor (CSF2/GMCSF)
    3. Prolactin family: PRL, GH Subfamily (GH1, GH2), Chorionic somatomammotropin Subfamily (CSH1, CSH2), Erythropoietin (EPO), Thrombopoietin (TPO), and Colony Stimulating Factor 3/Granulocyte-stimulating factor (CSF3/GCSF).
    4. IL-6 Family: IL-6, IL-11, IL-31, LIF, Ciliary Neurotrophic Factor (CNTF), Oncostatin M (OSM), and Cardiotrophin subfamily (CT1, CLC)
    5. IL-12 Family: IL-12, IL-23, IL-27/30, and IL-35
  2. Type II Cytokine families signaling through Class II cytokine receptors (CRF2 family or IL-10/IFN superfamily)
    1. L-10 Family: IL-10, IL-22, and IL-26
    2. IL-19 Family: IL-19, IL-20, and IL-24
    3. Type I IFN: IFN-α Family (IFN-α1, IFN-α2, IFN-α 4, IFN-α 5, IFN-α 6, IFN-α 7, IFN-α 8, IFN-α10, IFN-α13, IFN-α14, IFN-α16, IFN-α17, and IFN-α21)
    4. Type II IFN: IFN-γ, and IFN-λ Family (IFN-λ1/IL-29, IFN-λ2/IL-28A, IFNλ3/IL-28B, and IFN-λ4)
    5. IFN-β/ω: IFN-type I β/ω Family (IFN-β1 and IFN-ω1)
    6. Tissue Factor-VIIa system

Cytokine families signaling through immunoglobulin(Ig) superfamily cytokine receptors

  1. Receptor tyrosine kinase class III-ligands –RTKIII/PDGFR family: MCSF Family (CSF1/MCSF and IL-34), Flt3/Flk2, and Stem Cell Factor/KitL (SCF/KitL)
    1. CSF1/MCSF
    2. IL-34
    3. FLT3LG (Fms-like tyrosine kinase 3 ligands)
    4. Stem Cell Factor(SCF)/KitL
  2. non-Receptor tyrosine-kinase(RTK)
    1. IL-1 Family: IL-1s, IL-18, IL-33, IL-36, IL-37, and IL-38
    2. IL-16
    3. HMG1B (High Mobility Group 1B)

Cytokine TNF family signaling through TNF receptor family

  1. LTA/TNFSF1, TNF-α/TNFSF2, LTB/TNFSF3, OX40L/TNFSF4, CD40L/TNFSF5, FasL/TNFSF6, CD70/TNFSF7, CD30L/TNFSF-8, 4-1BBL/TNFSF-9, TRAIL/TNFSF10, RANKL/TNFSF11, TWEAK/TNFSF12, APRIL/TNFSF13, BLYS/TNFSF13B, LIGHT/TNFSF14, VEGI/TNFSF15, GITRL/TNFSF18, and EDA (Ectodysplasin).
  2. Non-TNF-ligand: Granulin/Epithelin (GRN) and Nerve Growth Factor (NGF).

Chemokine superfamily signaling through chemokine receptors (seven-transmembrane heptahelical (serpentine) receptors associated with G-protein trimeric system)

  1. Chemokine CC Motif Ligand Family (CCL): CCL1, CCL2, CCL3 Subfamily (CCL3, CCL3L1, and CCL3L3), CCL4 Subfamily (CCL4, CCL4L1, and CCL4L2), CCL5, CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, and CCL28
  2. Chemokine CXC Motif Ligand Family (CXCL): CXCL1, CXCL2, CXCL3, CXCL4 Subfamily(CXCL4/PF4 and CXCL4L1/PF4V1), CXCL5, CXCL6, CXCL7/PPBP, CXCL8/IL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL16, and CXCL17
  3. Chemokine XC Motif Ligand Family (XCL): XCL1 and XCL2
  4. Chemokine CX3C Motif Ligand (CXC3L)
  5. Other non-Chemokine ligands signaling through Chemokine receptors: Chemerin

Orphan and other cytokine family members

  1. IL-17 Family: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, and IL-17F.
  2. Other Cytokines: IL-14, IL-25/SF20, IL-32, MIF family (MIF1 and MIF2), Osteopontin (OPN), Thymic peptide family [Thymosin Family (Prothymosin-α, Thymosin-β4, Thymosin-β10, Thymosin-β15, and Parathymosin), and LEM Family (Thymopoietin)]

Growth factors and other glycoprotein hormones with immunological functions

  1. Insulin
  2. Cardiac Natriuretic Hormones/Natriuretic Peptides (CNH/NPs)
  3. TGF-β Superfamily members with immunological functions: TGF-β family (TGF-β1, TGFβ-2, and TGFβ-3), Activin family (Activin A, Activin B, and Activin AB), and GDF15/Mic1

Morphogen factors with immunological function

  1. Notch Receptor/Notch Receptor Ligand System: Notch Receptor Family (Notch1, Notch2, Notch3, and Notch4), Notch Receptor Ligand Jagged Subfamily (Jag1 and Jag2), Notch Receptor Ligand Delta-like Subfamily (DLL1, DLL3, and DLL4)
  2. Hedgehog (HH) system: SHH, IHH, DHH
  3. Wnt system

Adipokine functional family

Cytokines and cytokine-receptors general characteristics and properties

General Cytokine characteristics and properties are:

  • A functional network.
  • Usually, many cytokine families have evolved from common ancestral genes which, through mechanisms such as ancestral gene duplication, have created a wide variety of cytokines that often have the benefit of generating functional diversity.
  • Some cytokines are produced constitutively while others are inducible. Many of them are produced as pre-pro-cytokine or pro-cytokines, which require convertase-dependent processing for their activation.
  • Many have clearly inferred redundant actions; as a result, some cytokines carry out similar functions.
  • Many cytokines are immobilized in the extracellular matrix (ECM) by binding to proteoglycans (see Matricrine action example in the Introduction) (–).
  • Many cytokines will have different effects depending on the concentration and on whether or not their action is during the acute or chronic immune response phase. For example, Prolactin (PRL) has a dual effect, so low PRL concentrations stimulate T-lymphocytes, whereas high concentrations are anti-inflammatory/immunosuppressors.
  • A number of them are pleiotropic; therefore, they act on a wide variety of cell types.
  • They act on hematoinmune system cells as well as on almost any cell type in the body. Since they also function as metabolic modulators and response coordinators against systemic stressors within all tissues, organs, and body systems, some cytokines exert systemic effects that go beyond their immunoregulator role.
  • At any given time of life, a cell may have a wide variety of receptors to various cytokines.
  • Certain cytokines are read through products. This means that they are proteins decoded from contiguous genes. For example, TNFSF12-TNFSF13 read through genes produces a cytokine called TWEAKPRIL. In other situations, the contiguous cytokine gene mRNA transcripts probably encode miscRNA, which is a term used for a series of miscellaneous small RNA. The miRNA have a wide variety of functions, e.g., enzyme-like catalysis and processing after RNA synthesis. An example of this is the CCL15-CCL14 read-through gene chemokines (non-protein coding).
  • Some cytokines are capable of forming hybrids with other cytokines within the same or different families, which increases the response diversity, and signaling system versatility. These cytokines are called Hybridokines. For example, chemokine CXCL5-CCL5, or HGF/SF-IL7 heteromerization produces pre-pro-B cell growth-stimulating factor -PPBSF.
  • Typically, cytokine production tends to be local (tissue) and limited in time (transient) unless there is a pathological background phenomenon.
  • Many cytokines may be synergistic or antagonistic depending on the situation.
  • Cytokines may regulate or modulate the production/ activity of other cytokines.
  • A cytokine can have a differential effect on the same cell depending on the cell basal state (standby or activation) as well as the cell type and variety of expressed receptors. Moreover, one different cytokine could modulate the effect of another cytokine.
  • Some cytokines are pro-inflammatory, others anti-inflammatory (IL-2, IL-10, TGF-β family, IL-27, IL-35, and IL-37) or both (for example, IL-6), and others are regulatory, thus allowing tolerance to self – components as well as pathogen control and destruction with minimum tissue damage. For example, promoting the induction of immunocyte regulation (e.g., Treg, and the Breg) ().
  • There is an association between the heat immune and skeletal systems–a phenomenon called Osteoimmunology. Numerous proinflammatory cytokines affect bone cells as in the case of IL-1, IL-6, TNF-α, IL-8, IL-11, IL-15, IL-17, and IL-32 which are osteoclastogenic cytokines. In contrast, IFN-γ, IFN-β, IFN-α, IL-4, IL-10, IL-13, IL-18, and IL-33 are anti-osteoclastogenic. There are other cytokines with dual roles such as IL-17, IL-12, and IL-23. Note that the RANK-RANKL system is a member of the Tumor Necrosis Factor Superfamily-Tumor Necrosis Factor Superfamily Receptor system (TNFSF-TNFRSF) (–).
  • Cytokines are key factors in reproduction physiology through the regulation of specialized gonadal processes and during gestation ().
  • Many cytokines are endogenous molecules called alarmins. They are rapidly released after non-programmed cell death, but they are not released by apoptotic cells from injured tissues or as a result of stress. These cytokines promote the adaptive immune responses and restore homeostasis by promoting tissue reconstruction ().
  • Certain cytokines are rapidly inactivated by proteases such as the Neutral Serine Proteases (NSP) secreted by human polymorphonuclear neutrophils (PMNLs) and thus generate a negative feedback loop. So, for example, IL-2, IL6, and TNF-α are inactivated by human leukocyte elastase (HLE), proteinase 3 (PR3), or cathepsin G (Cat G). In other cases, proteases generate cytokine fragments that may function as antagonists of the active cytokines such as in the case of IL-2.
  • The hematopoietic cytokines have pro-and anti-angiogenic effects. pro-angiogenic cytokines are erythropoietin (EPO), Granulocyte-colony stimulating factor (GCSF), Granulocyte-macrophage colony-stimulating factor (GMCSF), IL-1, IL-3, IL-4, IL-6, IL-8, IL-10, IL-15, and IL-17. Some of the anti-angiogenic cytokines are IL-2, IL-4, IL-12, and IL-13 ().
  • The genome of certain viruses encodes cytokine-like molecules, which are referred to as “virokines.” They function as competitive inhibitors or competitive stimulators of host cytokine-receptors. So they subvert host immune responses and thereby favor the development of an infection-pathogenic scenario. Some examples are the vIL-6 (viral Interleukin 6) encoded by the Human Herpes Virus 8/Kaposi’s Sarcoma Virus genome (HHV8/KSV), vIL-8 encoded by Marek’s disease virus (MDV) genome, vIL-10/BCRF1 (Bam HI C fragment rightward reading frame 1) encoded by Human Herpes Virus 4/Epstein-Barr virus genome, vIL-10/UL111a (open reading frame) encoded by Human Herpes Virus 5/Citomegalovirus genome, and vIL-17 encoded by Herpesvirus saimiri genome, inter alia. The herpes virus and poxvirus family genome encode proteins that modulate chemokine activity, e.g., proteins with homology to chemokines or secreted chemokine-binding proteins (CKBPs). These CKBPs competitively interact with chemokines and prevent chemokine interactions with chemokine-receptors or the extracellular matrix. (See section chemokine superfamily signaling through chemokine receptors seven-transmembrane–heptahelical (serpentine) receptors associated with g-protein trimeric system) ().
  • Certain cytokines are found within biological fluids and are considered biomarkers for disease.
  • Cytokines have been used as contemporary therapeutic intervention targets. In some cases, they have been used to block or inhibit their own receptors or signalings pathways. In other cases, they have been used to stimulate the immune response (primary immunodeficiency, secondary immunodeficiency, severe infections, cancer, and vaccine adjuvant) or hematopoiesis (recombinant DNA technology) ().

Cytokines as well as other cell communication mediators are able to regulate various cell events within the cell, tissue, and system dynamics. Therefore, it is said that they can have many types of effects:

  • Geotropic: effect on gene expression regulation.
  • Metabotropic: metabolic process regulation.
  • Ionotropic: regulation of ion flow through cell membranes and related physiological processes.
  • Redoxtropic: oxidation-reduction potential regulation in the cell, which is also related to the physiological and pathological role of antioxidant neutralization and free radicals from reactive oxygen, nitrogen, and sulfur species (ROS/ROI, RNS/RNI, and RSS/RSI respectively).
  • Mitotropic, also know as mitogen cytokine: cell proliferative capacity regulation, but in addition to this function, they also regulate the entire cell cycle.
  • Morphogenic/morphogenetic, also know as morphogen cytokine: regulates ontogenetic development processes; commitment, proliferation, and differentiation during histogenesis; embryogenesis, ketogenesis, and organogenesis.
  • Motitropic/mitogenic, also called motogen cytokine: cytoskeletal activity regulation, cell motility capability, and cell contractility regulation. Some of these molecules are involved in the migration processes during embryogenesis and ketogenesis, e.g., operating through gradients as motomorphogens.
  • Trophotropic, or organotrophic factor, also known as morphogen cytokine: many cytokines such as growth factors favor cell and tissue tropism, which promotes their survival and proper function. Because of that, these cytokines are called morphogens.
  • Cytoprotection (against harmful and stressful agents) and reparation/regeneration factors.
  • Deathtropic: under certain circumstances, some cytokines are death cell signals (type I/apoptosis, type II/autophagy, type III/necrosis, or mixed/special states such as necroptosis, pyroptosis, and pyronecrosis, etc). The withdrawal of some cytokines also produces cell death, e.g., in the case of certain growth factors.

Throughout this section of the chapter, general cytokine characteristics and properties as well as the different effects they have on the cells or tissues have been discussed. Therefore, the general characteristics and properties of the Cytokine-receptors will be dealt with next (,):

  • The cytokine-receptors are (glyco) proteins signaling through different signal transduction mechanisms.
  • Usually, many cytokine-receptor families have evolved from common ancestral genes. Hence, a wide variety of cytokine-receptors have been created through mechanisms of ancestral gene duplication, often with the benefit of generating functional diversity.
  • In other cases, cytokine-receptors are obtained through secretion or exchange of membrane fragments between cells using mechanisms such as trogocytosis, formation of tunneling nanotubes (TNTs), and the release, secretion, and transportation of microvesicles (MVs)/Exosomes.
  • Cytokine-receptors satisfy the general properties of receptors including specificity, selectivity, induced fit (in previous scientific models, it is called lock-key model), desensitization/adaptation, signaling amplification, integration, saturability, and reversibility.
  • The receptors are usually located in specialized membrane microdomains known as lipid rafts, detergent-resistant membrane-DRM, and caveolae. These microdomains may be of various kinds depending on the variable presence of sphingolipids, glycosphingolipids, cholesterol, Glycosylphosphatidylinositol-proteins (GPI-linked), and certain specialized proteins such as caveolins (caveolin1, caveolin 2, and caveolin 3), Myelin and Lymphocyte protein (MAL) family members (MAL, MAL2, and MALL), and flotillins (FLOT1, and FLOT2). This is a way to centralize and coordinate the intracellular signaling platforms (receptor clustering). Moreover, note that there is even functional diversity when the receptor signals come either from inside of these domains or from outside of them (,).
  • Certain cytokine-receptors are numeric, and others are dimeric, oligomeric, or polymeric complexes. There is usually a cytokine-binding receptor and cytokine signaling-coreceptors in the dimeric, oligomeric or polymeric receptors.
  • Some receptors are part of polymeric complexes, in which several transmembrane proteins are recruited from different families including membrane proteoglycans (mPG) and CAMs (cell adhesion molecules) such as integrins. This is a key biological mechanism of receptor cross-talk (e.g., transphosphorylation) which generates a diversity of cell responses to a single ligand, even when there is an intracellular signaling modulation.
  • Some cytokine-receptors lack transmembrane and cytoplasmic domains. They function as scavengers, interceptors, and silent or decoy receptors and bind to ligands without inducing cell signaling. Many of these receptors are usually anchored to the cell surface via Glycosylphosphatidylinositol (GPI-linked). Some cytokine-receptors are kidnapper receptors acting via endocytosis, and some of them, in turn, are even in cytokine intracrine-pathways or cytokine-catabolisms.
  • Many receptors undergo the internalization and degradation that is dependent on the proteasome-ubiquitin route. Endocytic proteins that contain ubiquitin-interaction motifs (UIM) recognize the ubiquitylated receptors and direct them into clathrin-coated vesicles and, ultimately, into lysosomes. So, degradation is achieved through the action of the E3-ubiquitin-ligase Cbl member (Casitas B-lineage lymphoma proto-oncogene) family. In humans, four members of the Cbl-family are recognized: Cbl, CblB, CblC, and Cbll1 ().
  • Some cytokine-receptors, particularly receptor tyrosine kinase (RTK) type autocatalytic, are inhibited by the Sprouty (Spry) protein, which contains the SPRY/B30.2 homologous domain. Various human SPRY family members (SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3) and ERBB receptor feedback inhibitor 1/Mitogen-inducible gene 6 protein (ERRFI1/Mig6) modulate the actions of RTKs and have inhibitory effects on signal transduction. Spry proteins in some cases are genetically induced by the same cytokines, and in other cases, they are phosphorylated as part of the signaling cascade. This promotes their inhibitory action, in both cases as a feedback negative ().
  • There are soluble versions of some receptors which are produced from mRNA splicing and/or a receptor ectodomain undergoing shedding Regulated Intramembrane Proteolysis (RIP). During RIP cleavage are involved enzymes called “Sheddases” e.g., the MMPs, Adams (A Disintegrin and Metalloproteinase), and the gamma-secretase/presenilin complex are involved. Other examples are IL-2R, TNFRII, CSF1/MCSF-R, CD44, NOTCH-Receptors, and IL-6R shedding by PMN-serine proteases. These soluble versions function in some cases as decoy-receptors. In other cases, they act as binding soluble receptors carrying cytokines towards membrane receptors, or as conveyors. Likewise, the cytosolic fraction receptor-free or intracellular domain (ICD), functions as a transcription factor ().
  • Some receptors are not directly activated by binding their ligands. Activation occurs upon binding another ligand to its specific receptor. This phenomenon is called “Receptor transactivation,” and it refers to the ability of a ligand to bind to its specific receptor and thus activate another ligand-receptor. The mechanism involved during this process is transphosphorylation.
  • Some receptors are anchored to the membrane and are recognized as entry routes for certain infectious pathogenic agents. An example of this is the HGF/SF-R (Hepatocyte growth factor/scatter factor receptor), which is involved in the recognition and internalization of Listeria monocytogenes. A surface protein of this bacteria – internalin B (InlB) – interacts with the HGF/SF-R (Hepatocyte growth factor/scatter factor-receptor) and thus favors the entry of the bacteria. The chemokine-receptor Duffy antigen receptor for chemokines (DARC) serves as the erythroid receptor for the human malaria parasite (Plasmodium vivax) and the monkey malaria parasite (Plasmodium knowlesi). Another example is the Human immunodeficiency virus (HIV)-coreceptors by chemokine family (See chemokine superfamily signaling through chemokine receptors (seven-transmembrane –heptahelical(serpentine) receptors associated with g-protein trimeric system).
  • The cytokine-receptors suffer negative regulation by specialized inhibitory receptors, which belong to the Paired-receptor Superfamily. Some inhibitory receptors of this family are: SIRPα/CD172a, CD200R, CEACAM1/CD66a, 5 Leukocyte immunoglobulin-like receptor (LILR) members (LIR1/ILT2/CD85j, LIR2/ILT4/CD85d, LIR3/ILT5/CD85a, LIR5/ILT3/CD85K, and LIR8/CD85c), NKG2A/CD159a, DCIR/CLEC4A, CMRF35H/IREM1, PILRA, 12 Sialic acid-binding immunoglobulin-type lectin (SIGLE) family members (SIGLEC1, SIGLEC2/CD22, SIGLEC3/CD33, SIGLEC4/MAG, SIGLEC5, SIGLEC6/CD327, SIGLEC7/CD328, SIGLEC8, SIGLEC9/CD329, SIGLEC10, SIGLEC11, and SIGLEC12), and 8 Killer cell immunoglobulin-like receptor (KIR) family members (KIR2DL1/CD158a, KIR2DL2/CD158B1, KIR2DL3/CD158B2, KIR2DL5A/CD158F, KIR2DL5B/CD158F2, KIR3DL1/CD158E, KIR3DL2/CD158K, and KIR3DL3/CD158Z). These inhibitory receptors have immunoreceptor tyrosine-based inhibitory–motifs (ITIM) in their cytoplasmic region that upon receptor triggering, recruit cytosolic tyrosine-phosphatases ().
  • The genome of certain viruses encodes cytokine-receptor-like molecules referred as “receptors,” which function as competitive receptors of host cytokine-receptors. For example, herpes virus and poxvirus family genomes encoded a large number of proteins that modulate chemokine activity such as proteins with homology chemokine-receptors (See section chemokine superfamily signaling through chemokine receptors seven-transmembrane –heptahelical (serpentine) receptors associated with g-protein trimeric system) ().
  • Some receptors are part of the blood group system. The main example is the chemokine-receptor DARC (Duffy antigen receptor complex)/CD234. Therefore, variations in DARC generate the basis of the Duffy minor blood group system.
  • Some receptors are expressed abnormally in target cells, tissues, and organs involved in some diseases. Therefore, they can be considered pathophysiological and diagnostic biomarkers. The same happens with some soluble receptors when they are detected in biological fluids.
  • Within the current biological therapy, the use of soluble receptors produced by recombinant DNA technology emerges. An example of this is the biopharmaceutical molecule Etanercept (Enbrel ®), which was produced by the fusion of the Tumor Necrosis Factor Receptor (TNFR) protein linked to the IgG1 Fc portion of an antibody ().

Cytokines, cytokine receptors, and their signaling pathways specific characteristics and properties

Archetypical cytokine families signaling through class I cytokine receptors (CRF1 or hematopoietic family) and class II cytokine receptors (CRF2 or IL-10/IFN superfamily)

Type I cytokines have limited homology between the sequences of their family members. However, they are characterized by four α-helical bundle structures with an ‘up-up-down-down’ configuration. They can be further divided into short-chain and long-chain four α-helical bundle cytokines because of their α-helices length as well as some other structural and topological characteristics. Short-chain type I cytokines are those cytokines sharing the γc (gamma common chain) receptor, the βc (beta common chain) receptor, and also MCSF and SCF/KitL as atypical examples. Within of long-chain type I cytokines, there are cytokines sharing the gp130 common chain receptor, GH, Leptin, EPO, TPO, IL-12, PRL, and CSF3/GCSF. Unlike the type I cytokines, the type II cytokines have different structures and correspond to the members of the IL-10/IFN superfamily (–).

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CRF1 family members are characterized by conserved extracellular domains of approximately 200 amino acids, known as cytokine receptor homology domain (CHD), hematopoietic receptor domain (HRD), or D200. The CHD consists of two tandem fibronectin type III (FBN/FNIII) folds. It also contains two pairs of conserved cysteines (four conserved cysteines – C4) linked via disulfide-bonds, and it is arranged in a CX-(9–10)-CXWX-(26–32)-CX-(10–15)-C motif within the first FBN/FNIII fold. The second FBN/FNIII fold (proximal to the transmembrane domain) has a highly conserved tryptophan-serine doublet [(WS)2]=Trp-Ser-X-Trp-Ser motif (WSXWS-motif) in its carboxyl extreme. The C4 (WS) 2 motif represents a common signature to define Class I cytokine receptors. Additionally, this family has other module domains including the extracellular Ig-like, a transmembrane (TM) domain, and conserved intracellular motifs such as Box1- and Box2-motifs. These last two motifs are associated with cytosolic tyrosine Janus Kinase (JAK)-docking. These conserved intracellular motifs are part of the “Intracellular Homology Region (IHR) sequences”.

Jean-Louis Boulay, John J. O’Shea, and William E. Paul did a comparative study on the molecular phylogeny of type I cytokines and proposed that they be classified into 5 groups based on certain characteristics:

  • Group 1: receptor chains have an extracellular domain consisting solely of a CHD. For example, erythropoietin receptor (EPOR), thrombopoietin receptor (TPOR), prolactin receptor (PRLR), and growth hormone receptor (GHR) chains. Each of them produces homodimers in the presence of their respective ligands.
  • Group 2: receptors with polypeptidic chains structurally related to the prototypical glycoprotein 130 (gp130), which has an N-terminal Ig-domain and FBN modules between their CHD and transmembrane domains.
  • Group 3: receptor chains generally possess an N-terminal Ig domain in addition to the CHD. They are soluble and have short intracellular regions.
  • Group 4: receptors chains consist solely of an extracellular CHD domain and long intracellular domains.
  • Group 5: receptor chains possess extracellular Ig-domains in addition to the CHD and have short intracellular regions.
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Receptor chains from Groups 2 and 3 constitute the large IL-6R family receptor complexes, which variably share the gp130 as a common signal transducer. Group 4 and 5 receptor chains associate in order to generate the IL-2R and IL-3R family receptor complexes with IL-2Rγc and IL-3Rβc respectively. IL-2Rα and IL1-5Rα receptor chains are not members of the class I family receptors. Instead, they contain a distinctive ‘sushi domain’, also known as Complement control protein (CCP) modules or short consensus repeats (SCR) (–,).

However, for academic purposes, we proceeded to classify receptors and cytokine systems of this type as follows:

  • Family or Common gamma Chain Receptor Family: IL-2, IL-5, IL-9, IL-15, IL-21, IL-4 subfamily (IL-4 and IL-13), and IL-7 subfamily (IL-7 and TSLP).
  • Common beta Chain Receptor Cytokine Family: IL3, IL5, and CSF2/GMCSF.
  • Prolactin family: PRL, GH Subfamily (GH-1, and GH-2), CSH Subfamily (CSH-1 and CSH-2), EPO, TPO, and CSF3/GCSF
  • IL-6 Family: IL-6, IL-11, IL-31, LIF, CNTF, OSM, and Cardiotrophin subfamily (CT1 and CLC)
  • IL-12 Family: IL-12, IL-23, IL-27/30, and IL-35

Type II cytokines have different structures in comparison to type I. However, they retain the Box1/2 regions and they are classified as follows:

  • IL-10 Family: IL-10, IL-22, and IL-26.
  • IL-19 Family: IL-19, IL-20, and IL-24.
  • Type III: IFN- λ Family (IFN-λ1/IL-29, IFN-λ2/IL-28A, IFNλ3/IL-28B, and IFN-λ4).
  • Type I: IFN-α–IFN Family (IFN-α1, IFN-α2, IFN-α 4, IFN-α 5, IFN-α 6, IFN-α 7, IFN-α 8, IFN-α10, IFN-α13, IFN-α14, IFN-α16, IFN-α17, and IFN-α21).
  • Type II – IFN: IFN-γ.
  • Type I IFN-β/ω: IFN β/ω Family (IFN-β1 and IFN-ω1).
  • Tissue Factor – VIIa system.

References

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