Interleukins are low molecular weight proteins that bind to cell surface receptors and act in an autocrine and/or paracrine fashion. They were first identified as factors produced by leukocytes but are now known to be produced by many other cells throughout the body. They have pleiotropic effects on cells which bind them, impacting processes such as tissue growth and repair, hematopoietic homeostasis, and multiple levels of the host defense against pathogens where they are an essential part of the immune system.
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Vandenbroeck K, Alvarez J, Swaminathan B, Alloza I, Matesanz F, Urcelay E, Comabella M, Alcina A, Fedetz M, Ortiz MA, Izquierdo G, Fernandez O, Rodriguez-Ezpeleta N, Matute C, Caillier S, Arroyo R, Montalban X, Oksenberg JR, Antigüedad A, Aransay A.; ''A cytokine gene screen uncovers SOCS1 as genetic risk factor for multiple sclerosis.''; PubMedEurope PMCScholia
Nogami S, Satoh S, Nakano M, Shimizu H, Fukushima H, Maruyama A, Terano A, Shirataki H.; ''Taxilin; a novel syntaxin-binding protein that is involved in Ca2+-dependent exocytosis in neuroendocrine cells.''; PubMedEurope PMCScholia
Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, Chen S, Brand N, Tarway M, Liu L, Sheikh F, Astemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O'Brien TR.; ''A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.''; PubMedEurope PMCScholia
Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMedEurope PMCScholia
Novick D, Rubinstein M, Azam T, Rabinkov A, Dinarello CA, Kim SH.; ''Proteinase 3 is an IL-32 binding protein.''; PubMedEurope PMCScholia
Ryan TC, Cruikshank WW, Kornfeld H, Collins TL, Center DM.; ''The CD4-associated tyrosine kinase p56lck is required for lymphocyte chemoattractant factor-induced T lymphocyte migration.''; PubMedEurope PMCScholia
Zhou P, Devadas K, Tewari D, Jegorow A, Notkins AL.; ''Processing, secretion, and anti-HIV-1 activity of IL-16 with or without a signal peptide in CD4+ T cells.''; PubMedEurope PMCScholia
Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM.; ''IL-28, IL-29 and their class II cytokine receptor IL-28R.''; PubMedEurope PMCScholia
Zhang Y, Center DM, Wu DM, Cruikshank WW, Yuan J, Andrews DW, Kornfeld H.; ''Processing and activation of pro-interleukin-16 by caspase-3.''; PubMedEurope PMCScholia
Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT.; ''Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.''; PubMedEurope PMCScholia
Segaliny AI, Brion R, Mortier E, Maillasson M, Cherel M, Jacques Y, Le Goff B, Heymann D.; ''Syndecan-1 regulates the biological activities of interleukin-34.''; PubMedEurope PMCScholia
Ségaliny AI, Brion R, Brulin B, Maillasson M, Charrier C, Téletchéa S, Heymann D.; ''IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization.''; PubMedEurope PMCScholia
Liu Y, Cruikshank WW, O'Loughlin T, O'Reilly P, Center DM, Kornfeld H.; ''Identification of a CD4 domain required for interleukin-16 binding and lymphocyte activation.''; PubMedEurope PMCScholia
Tamada T, Honjo E, Maeda Y, Okamoto T, Ishibashi M, Tokunaga M, Kuroki R.; ''Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex.''; PubMedEurope PMCScholia
Nandi S, Cioce M, Yeung YG, Nieves E, Tesfa L, Lin H, Hsu AW, Halenbeck R, Cheng HY, Gokhan S, Mehler MF, Stanley ER.; ''Receptor-type protein-tyrosine phosphatase ζ is a functional receptor for interleukin-34.''; PubMedEurope PMCScholia
Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O'Mahony L, Palomares O, Rhyner C, Ouaked N, Schaffartzik A, Van De Veen W, Zeller S, Zimmermann M, Akdis CA.; ''Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases.''; PubMedEurope PMCScholia
Walter MR.; ''The molecular basis of IL-10 function: from receptor structure to the onset of signaling.''; PubMedEurope PMCScholia
Larsen A, Davis T, Curtis BM, Gimpel S, Sims JE, Cosman D, Park L, Sorensen E, March CJ, Smith CA.; ''Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains.''; PubMedEurope PMCScholia
Hiraoka O, Anaguchi H, Ota Y.; ''Evidence for the ligand-induced conversion from a dimer to a tetramer of the granulocyte colony-stimulating factor receptor.''; PubMedEurope PMCScholia
IL-32 has properties of a typical pro-inflammatory mediator, stimulating TNF-alpha, IL-1beta and IL-8 production, and activating the NF-kappaB and p38 mitogen-activated protein (MAP) kinase pathways. It is produced mainly by T, natural killer, epithelial and monocyte cells after stimulation by Interleukin-2, Interleukin-18 or IFN-gamma (Kim et al. 2005). IL-32 can bind proteinase 3, a neutrophil-derived serine protease, but its (assumed) receptor is unknown.
After ligand binding, IL1RL1 undergoes a conformational change, which allows the recruitment of IL1RAP. Structures are available for this minimal IL33 receptor complex (Lingel et al. 2009, Liu et al. 2013). Interleukin-33 (IL33), like IL1beta and IL18, is produced in a precursor form and can be cleaved by caspase-1. MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL33 stimulation.
Interleukin-1 receptor-like 1 (IL1RL1, ST2), known for many years to be an orphan receptor within the IL1 receptor family, can bind Interleukin-33 (IL33) (Schmitz et al. 2005). The functional IL33 receptor is a heteromeric receptor complex consisting of IL1RL1 and IL1RAP1 (Chackerian et al. 2007). IL33 is found constitutively in the nucleus of endothelial cells where it can bind histone H2A-H2B (Roussel et al. 2008) leading to poorly understood intracrine gene regulatory functions (Carriere et al. 2007, Martin et al. 2013). It can be passively released from damaged cells, hence it has been termed an alarmin or damage-associated molecular pattern (DAMP), though IL33 is also released by undamaged cells (Lefrancais & Cayrol 2012).
Full-length IL33 does not require proteolytic processing to become active (Martin & Martin 2016) but proteolytic processing by Cathepsin G (CSTG) and neutrophil elastase (ELANE) produces C-terminal peptides that are more active than the unprocessed full length protein. IL33 can be inactivated by the apoptotic caspases 3 and 7 (Luthi et al. 2009).
interleukin-34 (IL34) was identified as a potent activator of monocytes and macrophages, signaling through Colony-stimulating factor-1 (CSF1) receptor (CSF1R) with a distinct tissue distribution from CSF1 (Lin et al. 2008). IL34 and CSF1 share many functional properties. IL34 has no appreciable sequence similarity with any other protein but shares a four-helix bundle structure seen in CSF1 (Garceau et al. 2010, Liu et al. 2012). IL34 forms a noncovalently linked dimer (Ma et al. 2012) whereas CSF1 contains an intersubunit disulfide bond. The structure of the IL34:CSF1R complex shows a similar ligand-receptor assembly to that of CSF1:CSF1R.
Interferon lambda-1 (IFNL1) binds to its receptor Interleukin-10 receptor subunit beta (IL10RB) associated to Non-receptor tyrosine-protein kinase TYK2 (TYK2) and Interferon lambda receptor-1 associated to JAK1 (IFNLR1).
Interleukin-28A (IL28A, Interferon lambda 1), interleukin-28B (IL28B, Interferon lambda 2) and interleukin-29 (IFNL1, Interferon lambda 3) are related cytokines, collectively known as the type III interferons. They are distantly related to type I interferons (IFNs) are members of the class II cytokine family, which includes type I, II, and III interferons and the IL10 family (IL10, IL19, IL20, IL22, IL24, and IL26). They are encoded by genes that form a cluster on 19q13. Expression of all three can be induced by viral infection. They share a heterodimeric class II cytokine receptor that consists of interleukin 28 receptor alpha (IL28RA) and interleukin-10 receptor beta (IL10RB), which is also part of the receptor complexes for IL10, IL22, IL24 and IL26. IL28 and IL-29, like type I IFNs, can signal through ISRE regulatory sites. Therefore, it is likely they provide antiviral activity by the induction of at least a subset of IFN-stimulated genes.
The most important amino acids on the ligand for interaction with IL28RA are located in the AB loop: Lys49 and Arg51 in IFNL3 and Arg49 and His51 in IFNL2, respectively (Gad et al. 2010). Binding to IL-10RB is important via the helix D amino acids: Gly95 in IFNL3 and Val95 in IFNL2. The stability of the ternary interferon receptor complex might be central to explaining the differences between the IFNL cytokines, akin to that observed with IFNalpha (Vandenbroeck et al. 2012) This is black box event because still ther is not a complete model for the ligand–IL28RA–IL10RB complex.
The mature and biologically active secreted interleukin-16 (IL16) is a 13-kDa carboxy terminal peptide derived from a larger intracellular precursor protein. Cleavage of IL16 from the propeptide is mediated by caspase-3. IL16 is a chemoattractant for a variety of cell types that express the cell surface antigen CD4.
Interleukin-16 (IL16) does not contain a consensus secretory leader sequence, and the mechanism for its release has not been elucidated. Amino-terminal deletions of IL16 reduce its capacity for secretion (Zhou et al. 1999), but the significance of this is unclear.
CD4 is a receptor for Interleukin-16 (IL16), explaining how IL16 acts as a chemoattractant for a variety of CD4+ immune cells (Cruikshank et al. 2000, Cruikshank & Little 2008).
Signaling mediated by CD4 requires the amino acid sequence W345 to S350, located in the proximal end of the D4 domain. CD4 does not appear to require a co-receptor for IL16. Data from CD4 knockout mice suggests that there may be an additional IL16 receptor (Mathy et al. 2000).
Interleukin-14, renamed alpha-taxilin (TXLNA) was originally described as High molecular weight B-cell growth factor (Ambrus et al. 1994). TXLNA binds several forms of syntaxin (Nogami et al. 2003), but not when they are complexed with SNAP25, VAMP2 or STXBP1, suggesting that TXLNA interacts with syntaxins outside the SNARE complex. This observation and a predicted role in intracellular vesicle trafficking led to renaming of the gene. Txlna transgenic mice show a phenotype similar to systemic lupus erythematosus and Sjogren's syndrome (Shen et al. 2006).
FLT3 is a member of the Class III Receptor Tyrosine Kinase Family, which also includes FMS, KIT, PDGFRA and PDGFRB. It binds the cytokine FLT3LG (Hannum et al. 1994), which regulates differentiation, proliferation and survival of hematopoietic progenitor cells and dendritic cells.
FLT3LG is probably dimeric. Binding to monomeric FLT3 induces receptor dimerization (Verstraete et al. 2011, Grafone et al. 2012), which promotes phosphorylation of the tyrosine kinase domain, activating the receptor and consequently the downstream effectors. Early studies of FLT3 using a chimeric receptor composed of the extracellular domain of human FMS and the transmembrane and cytoplasmic domains of FLT3 demonstrated the activation of PLCG1, RASA1, SHC, GRB2, VAV, FYN, and SRC pathways. PLCG1, SHC, GRB2, and FYN were found to directly associate with the cytoplasmic domain of FLT3 (Dosil et al. 1993). Later studes using the full-length human receptor identified that FLT3LG binding to FLT3 leads to FLT3 autophosphorylation, association of FLT3 with GRB2, tyrosine phosphorylation of SHC and CBL, formation of a complex that includes CBL, the p85 subunit of PI3K and GAB2, and tyrosine phosphorylation of GAB1 and GAB2 and their association with PTPN11 (SHP-2) and GRB2. PTPN11 (SHP-2), but not PTPN6 (SHP-1) binds GRB2 directly and becomes tyrosine-phosphorylated in response to FLT3LG stimulation. INPP5D (SHIP) also becomes tyrosine-phosphorylated after FLT3LG stimulation but binds to SHC. GAB1 and GAB2 are rapidly tyrosine phosphorylated after FLT3LG stimulation of cells, interacting with tyrosine-phosphorylated PTPN11, p85 subunit of PI3K, GRB2, and SHC (Zhang & Broxmeyer 2000). GAB may mediate the downstream activation of PTPN11, PI3K and thereby PDK1 and AKt which activate the mTOR pathway (Grafone et al. 2012), and possibly the Ras/Raf/MAPK pathway. (Zhang et al. 1999, Marchetto et al. 1999, Zhang e& Broxmeyer 2000). Activation of FLT3 leads to limited activation of STAT5A via a JAK-independent mechanism (Zhang et al. 2000).
FLT3 is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Both types of mutation constitutively activate FLT3 (Small 2006).
The granulocyte colony-stimulating factor receptor (CSF3R, GCSFR, CD114) is a cell-surface receptor for the granulocyte colony-stimulating factor (CSF3, GCSF) (Larsen et al. 1990, Panapoulos & Watowich 2008). It is present on precursor cells in the bone marrow. CSF3 initiates cell proliferation and differentiation into mature neutrophilic granulocytes and macrophages.
CSF3 exists as a dimer and higher order oligomeric structures; only the dimer exhibits high affinity binding (Hiraoka & Anaguchi et al. 1994). CSF3R ligand-binding is associated with dimerization of the receptor (Aritomi et al. 1999, Tamada et al. 2006, Layton & Hall 2006) and signal transduction through Jak/STAT, Lyn and Erk1/2. Mutations in CSF3R are a cause of Kostmann syndrome, also known as severe congenital neutropenia (Zeidler & Welte 2002, Vandenberghe & Beel 2011).
The receptor for Interleukin-34 (IL34) is colony stimulating factor 1 receptor (CSF1R), also called macrophage colony stimulating factor receptor (M-CSF-R). Dimeric IL34 and CSF1 bind the same general region of CSF1R, interacting with overlapping but distinct epitopes. Ligand binding leads to receptor dimerisation (Ma et al. 2012, Liu et al. 2012). Like CSF1, IL34 stimulation of CSF1R leads to phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2 in human monocytes (Lin et al. 2008).
CSF1R activates several signaling pathways including JAK-STAT3, 5A/B, phosphorylation of PIK3R1, PLCG2, GRB2, SLA2 and CBL. PLCG2 phosphorylation leads to increassed production of the cellular signaling molecules diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3), which activate protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3 kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of MAPK1 (ERK2) or MAPK3 (ERK1) and the SRC family kinases SRC, FYN and YES1. Activated CSF1R binds GRB2 and promotes tyrosine phosphorylation of SHC1 and INPP5D (SHIP1). Signaling is down regulated by protein phosphatases such as INPP5D that can dephosphorylate the receptor and its downstream effectors.
After binding of IL36 to IL1RL2, the complex associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex. The IL-36 signaling system is thought to be present in epithelial barriers and to take part in local inflammatory response; it is similar to the IL-1 system (Gresnigt & van de Veerdonk 2013).
Interleukin-1 receptor-like 2 (IL1RL2) is a receptor for interleukin-36 (IL36A, IL36B and IL36G). After binding to interleukin-36 IL1RL2 associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex which mediates interleukin-36-dependent activation of NF-kappa-B, MAPK and other pathways. IL1RL2 also binds Interleukin-1 family member 10 (IL38, IL1F10) (van de Veerdonk et al. 2012). The biological function of IL1F10 is thought to be inhibition of IL36 binding to IL36R (Yuan et al. 2015, Yi et al. 2016).
Interleukin-37 (IL37) has the ability to non-competitively bind IL18R1 (Kumar et al. 2002, Buffer et al. 2002), making IL37 an inhibitor of IL-18 (Quirk & Agrawal 2014). IL37 may exist as a dimer (Kumar et al. 2002).
Interleukin-18 binding protein (IL18BP) is a constitutively secreted protein, with an exceptionally high affinity for IL18 (400 pM) (Kim et al. 2000). It is present in the serum of healthy humans at a 20-fold molar excess compared to IL18 (Novick et al. 2001) and may blunt the Th1 response to foreign organisms, thereby reducing any autoimmune responses to a routine infection (Dinarello et al. 2013).
IL18R1:IL18 binds Interleukin-18 receptor accessory protein (IL18RAP, IL18 receptor beta chain), forming a high affinity signaling complex (Born et al. 1998, Debets et al. 2001).
CSF3R ligand-binding is associated with dimerization of the receptor (Aritomi et al. 1999, Tamada et al. 2006, Layton & Hall 2006) and signal transduction through Jak/STAT, Lyn and Erk1/2.
Interleukin-36 receptor antagonist protein (IL36RN, IL-36Ra) binds the interleukin-36 receptor subunit IL1RL2 (Interleukin-1 receptor-like 2, IL-1Rrp2). This inhibits the activity of interleukin-36 (IL36) by preventing IL1RL2 and IL1RAP from associating to form the interleukin-36 receptor complex (Towne et al. 2015). Similarly, Interleukin-1 family member 10 (IL1F10), also referred to as Interleukin-38, binds the interleukin-36 receptor subunit IL1RL2 inhibiting IL36 signaling (van de Veerdonk et al. 2012).
Homozygous and compound heterozygous mutations in IL36RN have been identified to cause generalized pustular psoriasis (GPP) (Onoufriadis et al. 2011, Marrakchi et al. 2011).
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Full-length IL33 does not require proteolytic processing to become active (Martin & Martin 2016) but proteolytic processing by Cathepsin G (CSTG) and neutrophil elastase (ELANE) produces C-terminal peptides that are more active than the unprocessed full length protein. IL33 can be inactivated by the apoptotic caspases 3 and 7 (Luthi et al. 2009).
Interleukin-28A (IL28A, Interferon lambda 1), interleukin-28B (IL28B, Interferon lambda 2) and interleukin-29 (IFNL1, Interferon lambda 3) are related cytokines, collectively known as the type III interferons. They are distantly related to type I interferons (IFNs) are members of the class II cytokine family, which includes type I, II, and III interferons and the IL10 family (IL10, IL19, IL20, IL22, IL24, and IL26). They are encoded by genes that form a cluster on 19q13. Expression of all three can be induced by viral infection. They share a heterodimeric class II cytokine receptor that consists of interleukin 28 receptor alpha (IL28RA) and interleukin-10 receptor beta (IL10RB), which is also part of the receptor complexes for IL10, IL22, IL24 and IL26.
IL28 and IL-29, like type I IFNs, can signal through ISRE regulatory sites. Therefore, it is likely they provide antiviral activity by the induction of at least a subset of IFN-stimulated genes.
The most important amino acids on the ligand for interaction with IL28RA are located in the AB loop: Lys49 and Arg51 in IFNL3 and Arg49 and His51 in IFNL2, respectively (Gad et al. 2010).
Binding to IL-10RB is important via the helix D amino acids: Gly95 in IFNL3 and Val95 in IFNL2.
The stability of the ternary interferon receptor complex might be central to explaining the differences between the IFNL cytokines, akin to that observed with IFNalpha (Vandenbroeck et al. 2012)
This is black box event because still ther is not a complete model for the ligand–IL28RA–IL10RB complex.
FLT3LG is probably dimeric. Binding to monomeric FLT3 induces receptor dimerization (Verstraete et al. 2011, Grafone et al. 2012), which promotes phosphorylation of the tyrosine kinase domain, activating the receptor and consequently the downstream effectors. Early studies of FLT3 using a chimeric receptor composed of the extracellular domain of human FMS and the transmembrane and cytoplasmic domains of FLT3 demonstrated the activation of PLCG1, RASA1, SHC, GRB2, VAV, FYN, and SRC pathways. PLCG1, SHC, GRB2, and FYN were found to directly associate with the cytoplasmic domain of FLT3 (Dosil et al. 1993). Later studes using the full-length human receptor identified that FLT3LG binding to FLT3 leads to FLT3 autophosphorylation, association of FLT3 with GRB2, tyrosine phosphorylation of SHC and CBL, formation of a complex that includes CBL, the p85 subunit of PI3K and GAB2, and tyrosine phosphorylation of GAB1 and GAB2 and their association with PTPN11 (SHP-2) and GRB2. PTPN11 (SHP-2), but not PTPN6 (SHP-1) binds GRB2 directly and becomes tyrosine-phosphorylated in response to FLT3LG stimulation. INPP5D (SHIP) also becomes tyrosine-phosphorylated after FLT3LG stimulation but binds to SHC. GAB1 and GAB2 are rapidly tyrosine phosphorylated after FLT3LG stimulation of cells, interacting with tyrosine-phosphorylated PTPN11, p85 subunit of PI3K, GRB2, and SHC (Zhang & Broxmeyer 2000). GAB may mediate the downstream activation of PTPN11, PI3K and thereby PDK1 and AKt which activate the mTOR pathway (Grafone et al. 2012), and possibly the Ras/Raf/MAPK pathway. (Zhang et al. 1999, Marchetto et al. 1999, Zhang e& Broxmeyer 2000). Activation of FLT3 leads to limited activation of STAT5A via a JAK-independent mechanism (Zhang et al. 2000).
FLT3 is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Both types of mutation constitutively activate FLT3 (Small 2006).