What Are Interleukins

Interleukin Definition

Cytokines play a very important role in nearly all aspects of inflammation and immunity. Interleukins are a type of cytokines that were first seen to be expressed by leukocytes. The term 'interleukin' was first coined in 1979 in a letter to the editor of the Journal of Immunology to describe a number of secreted molecules produced by leukocytes, a variety of polypeptides that act specifically as mediators between leucocytes. However, the name interleukin is something of a relic, since it has been found that interleukins are produced by a wide variety of body cells. A number of groups have tried to classify members of this gene family by a variety of characteristics, including biological function, receptor-binding properties, sequence homology, common structural motifs and the cell types responsible for their production.

This has resulted in a number of nomenclature systems and has led to a great deal of confusion when describing individual genes and gene families. A common interleukin nomenclature system was approved by the International Union of Immunological Societies (IUIS) and the World Health Organization Nomenclature Subcommittee for IL1 - IL10 , including IL1A and IL1B. Designations for IL11 - IL13 were approved and updated by IUIS/WHO in 1994, IL16 in 1996 and IL14 - IL15 in 1997. Sims and colleagues recommended a new nomenclature system in 2001 for IL1 family genes. This nomenclature scheme was based on peptide sequence conservation, common structural elements, gene architecture and publication date.

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Interleukin Function

The term 'interleukin' (IL) has been used to describe a group of cytokines with complex immunomodulatory functions - including cell proliferation, maturation, migration and adhesion. These cytokines also play an important role in immune cell differentiation and activation. Determining the exact function of a particular cytokine is complicated by the influence of the producing cell type, the responding cell type and the phase of the immune response. ILs can also have pro- and anti-inflammatory effects, further complicating their characterisation. These molecules are under constant pressure to evolve due to continual competition between the host's immune system and infecting organisms; as such, ILs have undergone significant evolution. This has resulted in little amino acid conservation between orthologous proteins, which further complicates the gene family organisation.

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Interleukins are a large group of immunomodulatory proteins that elicit a wide variety of responses in cells and tissues. These cytokines comprise a large number of the known immunological 'second messenger' molecules within mammals. Interleukins initiate a response by binding to high-affinity receptors located on the surface of cells; Interleukins function in a paracrine or autocrine fashion, rather than as an endocrine signal, which is more common with steroidal and amino acid-derived hormones. The response of a particular cell to these cytokines depends on the ligands involved, specific receptors expressed on the cell surface and the particular signalling cascades that are activated. ILs modulate growth, differentiation and activation during an immune response. This distinguishes them from chemokines - the main function of which is to direct immune cells to the site of inflammation via chemotaxis - and interferons (IFNs), which predominantly mediate cellular response to viral infection. Despite attempts to separate these three groups based on function, there is a degree of overlap.

Interleukins can exert both inflammatory and anti- inflammatory actions. A few members act as chemoattractants for helper T cells, paralleling the actions of chemokines. Others are intimately involved in the cellular response to viral pathogens, making them akin to IFNs. ILs are very important mediators of the physiological response to infection and also contribute significantly to the pathophy- siology of a wide range of disorders. As such, interleukins can function as potential therapeutic targets.

Interleukin Function Table

Cytokine Cytokine Receptor Cytokine Source Cytokine Targets Cytokine Main Function Cytokine Disease Association
IL-1α; IL-1b IL1RI and IL1R-AcP Macrophages, many others Macrophages, thymocytes, CNS, others Inflammatory; promotes activation, costimulation, and secretion of cytokines and other acute-phase proteins; pyrogenic ↑ = inflammatory bone resorption; gout; promotes Th17 response
IL-1ra (antagonist) Soluble decoyreceptor: IL1RII and IL1R-AcP     IL-1ra and the soluble decoy receptor complex inhibit IL-1-mediated inflammatory responses  
IL-2 IL2Rα, IL2Rb, and IL2Rγ T cells T, B, NK cells, and macrophages Proliferation; enhancement of cytotoxicity, IFNγ secretion, and antibody production ↓ = lymphoproliferative disease and susceptibility to autoimmune disease; reduced Treg development. ↑ = reduced Th17 development.
IL-3 IL3Rα and IL3Rb T cells, mast cells, eosinophils Hematopoietic progenitors, macro- phages, mast cells Differentiation and survival of lymphoid and myeloid compartment  
IL-4 IL4Rα and IL2Rγ or IL4Rα and IL13Ra1, IL13Ra2 T cells, mast cells T cells, B cells, macrophages, monocytes Proliferation; differentiation of Th2; promotes IgG and IgE production; inhibits cell-mediated immunity and Th17 development ↓ = susceptibility to extracellular pathogens and decreased response to allergens. ↑ = allergic asthma.
IL-5 IL5Rα and IL3Rb Th2 cells Eosinophils, B cells Proliferation and activation; hallmark of Th2 effector cells ↓ = eosinophil and B-1 cell deficiency. ↑ = allergic asthma.
IL-6 IL6Rα and gp130 Macrophages, T cells, fibroblasts, and others Wide variety of cells: B cells, T cells, thymocytes, myeloid cells, osteoclasts Inflammatory and costimulatory action; induces proliferation and differentiation; synergizes with TGFb to drive Th17 ↓ = deficient innate immunity and acute- phase responses, lymphopenia
IL-7 IL7Rα and IL2Rγ Thymic stromal cells, bone marrow, and spleen B cells, T cells, thymocytes Homeostasis, differentia- tion, and survival ↓ = severe combined immune deficiency (SCID)
IL-9 IL9R and IL2Rγ T cells (Th2) T cells, mast cells, neutrophils, epithelial cells Proliferation; promotes Th2 cytokine secretion  
IL-10 IL10R1 and IL10R2 Differentiated T helper cells, Tregs, B cells, dendritic cells, others Macrophages, T cells, dendritic cells, B cells Immune suppression; decreases antigen presentation and MHC class II expression of dendritic cells; down- regulates pathogenic Th1, Th2, and Th17 responses ↓ = immune pathology due to uncon- trolled inflammation. ↑ = inhibits sterile immunity to some pathogens.
IL-11 IL11Rα and gp130 Stromal cells Hematopoietic stem cells, B cells, megakaryocytes Proliferation ↑ = exacerbates airway diseases
IL-12 (p35 + p40) IL12Rb1 and IL12Rb2 Macrophages, dendritic cells, B cells, neutrophils T cells, NK cells Differentiation and proliferation; promotes Th1 and cytotoxicity ↓ = impaired Th1 responses and increased susceptibility to intracellular pathogens
IL-13 IL13Ra1, IL13Ra2 and IL4Rα T cells B cells, macro- phages, others Goblet cell activation in lung and gut; proliferation and promotion of IgE production; regulation of cell-mediated immunity ↓ = impaired Th2 responses to extracel- lular pathogens and allergens. ↑ = exacerbates airway diseases.
IL-14 Not defined T cells B cells Promotion of B cell growth  
IL-15 IL15Rα, IL2Rb, and IL2Rγ Broad expression in hematopoietic cells T cells, NK cells, epithelial cells, others Proliferation and survival; cytokine production ↓ = deficiency in NK cells and defective generation of memory T cells
IL-16 Not defined T cells, eosinophils, mast cells CD4+ T cells Recruitment of CD4+ T cells  
IL-17A IL17RA or IL17RC Th17 cells and others Mucosal tissues, epithelial and endothelial cells Proinflammatory; protective immunity in lung; tight junction integrity; promotes mobilization of neutrophils and cytokine production by epithelial cells; promotes angiogenesis ↓ = susceptibility to extracellular pathogens ↑ = exacerbates organ- specific autoimmune inflammation
IL-17B   Intestine and pancreas      
IL- 17C   thymus and spleen      
IL-17D   T cells, smooth muscle cells, epithelial cells      
IL-17F IL17RA or IL17RC Th17 cells Mucosal tissues, epithelial and endothelial cells Similar function as IL-17A but with 2 logs lower receptor affinity Not well defined. ↑ = increases neutrophil recruit- ment at high concentration.
IL-18 IL18R and IL18-R-AcP Macrophages, others Th1 cells, NK cells, B cells Proinflammatory; induction of IFNγ ↓ = impairs Th1 responses
IL-19 IL20R1 and IL20R2 Monocytes, others Keratinocytes, other tissues Proinflammatory ↑ = psoriasis
IL-20 IL20R1 or IL22R1 and IL20R2 Monocytes, others Keratinocytes, other tissues Proinflammatory ↑ = psoriasis
IL-21 IL21R and IL2Rγ Differentiated T helper cells (Th2 and Th17 subsets) T cells, B cells, NK cells, dendritic cells Proliferation of T cells; promotes differentia- tion of B cells and NK cytotoxicity  
IL-22 IL22R1 and IL10R2; IL22BP Th1 and Th17 cells, NK cells Fibroblasts, epithelial cells Inflammatory, antimicrobial ↑ = psoriasis
IL-23 (p19 + p40) IL23R and IL12Rb1 Macrophages and dendritic cells T cells Inflammatory; promotes proliferation of Th17 cells ↓ = susceptibility to extracellular pathogens. ↑ = exacerbates organ- specific autoimmune inflammation.
IL-24 IL20R1, IL22R1, IL20R2 Monocytes, CD4+ T cells Keratinocytes   ↑ = antitumor effects
IL-25 (IL-17E) IL17RB Th2 cells, mast cells Non-B, non-T, cKit+, FcεR− cells Promotes Th2 differentiation and proliferation ↓ = impairs Th2 responses to extracellular pathogens such as worms
IL-26 IL22R1 and IL10R2 Activated T cells      
IL-27 (p28 + EBI3) WSX-1 and gp130 Activated dendritic cells T cells, others Induction of early Th1 differentiation by stimulating expression of the Tbet transcrip- tion factor; Inhibition of effector Th17 cel responses by inducing STAT-1-dependent blockade of IL-17 production ↓ = immune pathology due to uncontrolled inflamma- tory response
IL-28A/B/IL29 (IFNλ family) IL28R1 and IL10R2 Activated subsets of dendritic cells?   May promote antiviral responses  
IL-30 (p28 subunit of IL-27)          
IL-31 IL31Rα and OSM-Rβ Activated T cells Myeloid progenitors, lung epithelial cells, keratinocytes Proinflammatory ↑ = atopic dermatitis; allergic asthma
IL-32       Induces proinflammatory cytokine production  
IL-33 ST2 and IL1R-AcP Macrophages, dendritic cells Mast cells, Th2 cells Costimulation, promotes Th2 cytokine production ↑ = atopic dermatitis, allergic asthma
IL-35 (p35 + EBI3)   Tregs Effector T cells Immune suppression  


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