The interleukin-20 (IL20) subfamily comprises IL19, IL20, IL22, IL24 and IL26. They are members of the larger IL10 family, but have been grouped together based on their usage of common receptor subunits and similarities in their target-cell profiles and biological functions. Members of the IL20 subfamily facilitate the communication between leukocytes and epithelial cells, thereby enhancing innate defence mechanisms and tissue repair processes at epithelial surfaces. Much of the understanding of this group of cytokines is based on IL22, which is the most studied member (Rutz et al. 2014).
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Braunstein J, Brutsaert S, Olson R, Schindler C.; ''STATs dimerize in the absence of phosphorylation.''; PubMedEurope PMCScholia
Wang M, Tan Z, Zhang R, Kotenko SV, Liang P.; ''Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2.''; PubMedEurope PMCScholia
Novak AJ, Grote DM, Ziesmer SC, Rajkumar V, Doyle SE, Ansell SM.; ''A role for IFN-lambda1 in multiple myeloma B cell growth.''; PubMedEurope PMCScholia
Floss DM, Klöcker T, Schröder J, Lamertz L, Mrotzek S, Strobl B, Hermanns H, Scheller J.; ''Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases.''; PubMedEurope PMCScholia
Logsdon NJ, Deshpande A, Harris BD, Rajashankar KR, Walter MR.; ''Structural basis for receptor sharing and activation by interleukin-20 receptor-2 (IL-20R2) binding cytokines.''; PubMedEurope PMCScholia
Donnelly RP, Sheikh F, Dickensheets H, Savan R, Young HA, Walter MR.; ''Interleukin-26: an IL-10-related cytokine produced by Th17 cells.''; PubMedEurope PMCScholia
Walter MR.; ''The molecular basis of IL-10 function: from receptor structure to the onset of signaling.''; PubMedEurope PMCScholia
Haan C, Kreis S, Margue C, Behrmann I.; ''Jaks and cytokine receptors--an intimate relationship.''; PubMedEurope PMCScholia
Tritsaris K, Myren M, Ditlev SB, Hübschmann MV, van der Blom I, Hansen AJ, Olsen UB, Cao R, Zhang J, Jia T, Wahlberg E, Dissing S, Cao Y.; ''IL-20 is an arteriogenic cytokine that remodels collateral networks and improves functions of ischemic hind limbs.''; PubMedEurope PMCScholia
Gallagher G, Dickensheets H, Eskdale J, Izotova LS, Mirochnitchenko OV, Peat JD, Vazquez N, Pestka S, Donnelly RP, Kotenko SV.; ''Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10).''; PubMedEurope PMCScholia
Ferrao R, Lupardus PJ.; ''The Janus Kinase (JAK) FERM and SH2 Domains: Bringing Specificity to JAK-Receptor Interactions.''; PubMedEurope PMCScholia
Rutz S, Wang X, Ouyang W.; ''The IL-20 subfamily of cytokines--from host defence to tissue homeostasis.''; PubMedEurope PMCScholia
Ferrao R, Wallweber HJ, Ho H, Tam C, Franke Y, Quinn J, Lupardus PJ.; ''The Structural Basis for Class II Cytokine Receptor Recognition by JAK1.''; PubMedEurope PMCScholia
Xu W, Presnell SR, Parrish-Novak J, Kindsvogel W, Jaspers S, Chen Z, Dillon SR, Gao Z, Gilbert T, Madden K, Schlutsmeyer S, Yao L, Whitmore TE, Chandrasekher Y, Grant FJ, Maurer M, Jelinek L, Storey H, Brender T, Hammond A, Topouzis S, Clegg CH, Foster DC.; ''A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist.''; PubMedEurope PMCScholia
Lee SJ, Lee EJ, Kim SK, Jeong P, Cho YH, Yun SJ, Kim S, Kim GY, Choi YH, Cha EJ, Kim WJ, Moon SK.; ''Identification of pro-inflammatory cytokines associated with muscle invasive bladder cancer; the roles of IL-5, IL-20, and IL-28A.''; PubMedEurope PMCScholia
Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE.; ''Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions.''; 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
Sheikh F, Baurin VV, Lewis-Antes A, Shah NK, Smirnov SV, Anantha S, Dickensheets H, Dumoutier L, Renauld JC, Zdanov A, Donnelly RP, Kotenko SV.; ''Cutting edge: IL-26 signals through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2.''; PubMedEurope PMCScholia
Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD.; ''Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15.''; PubMedEurope PMCScholia
Jain S, Gabunia K, Kelemen SE, Panetti TS, Autieri MV.; ''The anti-inflammatory cytokine interleukin 19 is expressed by and angiogenic for human endothelial cells.''; PubMedEurope PMCScholia
Doyle SE, Schreckhise H, Khuu-Duong K, Henderson K, Rosler R, Storey H, Yao L, Liu H, Barahmand-pour F, Sivakumar P, Chan C, Birks C, Foster D, Clegg CH, Wietzke-Braun P, Mihm S, Klucher KM.; ''Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes.''; PubMedEurope PMCScholia
Wehinger J, Gouilleux F, Groner B, Finke J, Mertelsmann R, Weber-Nordt RM.; ''IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes.''; PubMedEurope PMCScholia
Pletnev S, Magracheva E, Kozlov S, Tobin G, Kotenko SV, Wlodawer A, Zdanov A.; ''Characterization of the recombinant extracellular domains of human interleukin-20 receptors and their complexes with interleukin-19 and interleukin-20.''; PubMedEurope PMCScholia
Hör S, Pirzer H, Dumoutier L, Bauer F, Wittmann S, Sticht H, Renauld JC, de Waal Malefyt R, Fickenscher H.; ''The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains.''; PubMedEurope PMCScholia
Yoon SI, Jones BC, Logsdon NJ, Harris BD, Deshpande A, Radaeva S, Halloran BA, Gao B, Walter MR.; ''Structure and mechanism of receptor sharing by the IL-10R2 common chain.''; PubMedEurope PMCScholia
Akdis M, Aab A, Altunbulakli C, Azkur K, Costa RA, Crameri R, Duan S, Eiwegger T, Eljaszewicz A, Ferstl R, Frei R, Garbani M, Globinska A, Hess L, Huitema C, Kubo T, Komlosi Z, Konieczna P, Kovacs N, Kucuksezer UC, Meyer N, Morita H, Olzhausen J, O'Mahony L, Pezer M, Prati M, Rebane A, Rhyner C, Rinaldi A, Sokolowska M, Stanic B, Sugita K, Treis A, van de Veen W, Wanke K, Wawrzyniak M, Wawrzyniak P, Wirz OF, Zakzuk JS, Akdis CA.; ''Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases.''; PubMedEurope PMCScholia
Gad HH, Dellgren C, Hamming OJ, Vends S, Paludan SR, Hartmann R.; ''Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family.''; PubMedEurope PMCScholia
Tian Y, Sommerville LJ, Cuneo A, Kelemen SE, Autieri MV.; ''Expression and suppressive effects of interleukin-19 on vascular smooth muscle cell pathophysiology and development of intimal hyperplasia.''; PubMedEurope PMCScholia
Sestito R, Madonna S, Scarponi C, Cianfarani F, Failla CM, Cavani A, Girolomoni G, Albanesi C.; ''STAT3-dependent effects of IL-22 in human keratinocytes are counterregulated by sirtuin 1 through a direct inhibition of STAT3 acetylation.''; PubMedEurope PMCScholia
Parrish-Novak J, Xu W, Brender T, Yao L, Jones C, West J, Brandt C, Jelinek L, Madden K, McKernan PA, Foster DC, Jaspers S, Chandrasekher YA.; ''Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions.''; PubMedEurope PMCScholia
Dumoutier L, Lejeune D, Colau D, Renauld JC.; ''Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22.''; PubMedEurope PMCScholia
Vignali DA, Kuchroo VK.; ''IL-12 family cytokines: immunological playmakers.''; PubMedEurope PMCScholia
Jones BC, Logsdon NJ, Walter MR.; ''Structure of IL-22 bound to its high-affinity IL-22R1 chain.''; PubMedEurope PMCScholia
Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, Wood WI, Goddard AD, Gurney AL.; ''Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R.''; PubMedEurope PMCScholia
Dumoutier L, Tounsi A, Michiels T, Sommereyns C, Kotenko SV, Renauld JC.; ''Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling.''; PubMedEurope PMCScholia
Yoon SI, Logsdon NJ, Sheikh F, Donnelly RP, Walter MR.; ''Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex.''; PubMedEurope PMCScholia
Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T.; ''Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway.''; PubMedEurope PMCScholia
Sainz-Perez A, Gary-Gouy H, Gaudin F, Maarof G, Marfaing-Koka A, de Revel T, Dalloul A.; ''IL-24 induces apoptosis of chronic lymphocytic leukemia B cells engaged into the cell cycle through dephosphorylation of STAT3 and stabilization of p53 expression.''; PubMedEurope PMCScholia
Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S.; ''Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity.''; PubMedEurope PMCScholia
You W, Tang Q, Zhang C, Wu J, Gu C, Wu Z, Li X.; ''IL-26 promotes the proliferation and survival of human gastric cancer cells by regulating the balance of STAT1 and STAT3 activation.''; PubMedEurope PMCScholia
Liu L, McBride KM, Reich NC.; ''STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3.''; PubMedEurope PMCScholia
Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC.; ''Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10.''; PubMedEurope PMCScholia
Andoh A, Shioya M, Nishida A, Bamba S, Tsujikawa T, Kim-Mitsuyama S, Fujiyama Y.; ''Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease.''; PubMedEurope PMCScholia
Meng S, Gui Q, Xu Q, Lu K, Jiao X, Fan J, Ge B, Ke Y, Zhang S, Wu J, Wang C.; ''Association of Shp2 with phosphorylated IL-22R1 is required for interleukin-22-induced MAP kinase activation.''; PubMedEurope PMCScholia
Li J, Tomkinson KN, Tan XY, Wu P, Yan G, Spaulding V, Deng B, Annis-Freeman B, Heveron K, Zollner R, De Zutter G, Wright JF, Crawford TK, Liu W, Jacobs KA, Wolfman NM, Ling V, Pittman DD, Veldman GM, Fouser LA.; ''Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2.''; PubMedEurope PMCScholia
Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi M, Taga T, Kishimoto T.; ''Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family.''; PubMedEurope PMCScholia
Finbloom DS, Winestock KD.; ''IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes.''; PubMedEurope PMCScholia
Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, Eagan M, Foster D, Haldeman BA, Hammond A, Haugen H, Jelinek L, Kelly JD, Madden K, Maurer MF, Parrish-Novak J, Prunkard D, Sexson S, Sprecher C, Waggie K, West J, Whitmore TE, Yao L, Kuechle MK, Dale BA, Chandrasekher YA.; ''Interleukin 20: discovery, receptor identification, and role in epidermal function.''; PubMedEurope PMCScholia
Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T.; ''New microRNAs from mouse and human.''; PubMedEurope PMCScholia
Naeger LK, McKinney J, Salvekar A, Hoey T.; ''Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling.''; 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
Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC.; ''Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types.''; PubMedEurope PMCScholia
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
The extracellular signal regulated kinases (ERKs) 1 and 2, also known as MAPK3 and MAPK1, are phosphorylated by the MAP2Ks 1 and 2 in response to a wide range of extracellular stimuli to promote differentiation, proliferation, cell motility, cell survivial, metabolism and transcription, among others (reviewed in Roskoski, 2012b; McKay and Morrison, 2007; Raman et al, 2007). In the classical pathway, MAPK1/3 activation is triggered by the GEF-mediated activation of RAS at the plasma membrane, leading to the activation of the RAF MAP3Ks (reviewed in McKay and Morrison, 2007; Matallanas et al, 2011; Wellbrock et al, 2004). However, many physiological and pathological stimuli have been found to activate MAPK1/3 independently of RAF and RAS, acting instead through MAP3Ks such as MOS, TPL2 and AMPK (Dawson et al, 2008; Wang et al, 2009; Kuriakose et al, 2014; Awane et al, 1999). Activated MAPK1/3 phosphorylate numerous targets in both the nucleus and cytoplasm (reviewed in Yoon and Seger, 2006; Roskoski 2012b).
The Interleukin-22 receptor is a heterodimer of Interleukin-22 receptor subunit alpha-1 (IL22RA1) and Interleukin-10 receptor subunit beta (IL10RB), a component of the receptors for Interleukin-10 (IL10), Interleukin-22 (IL22), Interleukin-26 (IL26), Interleukin-28 (IL28), and Interferon lambda-1 (IFNL1). Temporal models suggest that the first event in IL22 receptor formation is binding of Interleukin-22 (IL22) to IL22RA (Li et al. 2004).
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.
Interleukin-20 (IL20) and Interleukin-24 (IL24) can activate a heterodimer of Interleukin-22 receptor subunit alpha-1 or 2 (IL22RA1 or IL22RA2) and Interleukin-20 receptor B (IL20RB) (Dumoutier et al. 2001, Parrish-Novak et al. 2002). As it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
Interleukin-19 (IL19) binds a heterodimeric receptor complex formed by Interleukin-20 Receptor subunit alpha (IL20RA) associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB). Interleukin-20 receptor A (IL20RA) and Interleukin-20 receptor B (IL20RB) form a receptor complex for Interleukin-19 (IL19) (and also Interleukin-20 (IL20) and Interleukin-24 (IL24)) (Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014, Pletnev et al. 2003). This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
Interleukin-22 receptor subunit alpha-2 (IL22RA2), also known as Interleukin-22 binding protein (IL22BP), is a soluble receptor that binds Interleukin-22 (IL22) within the extracellular region, preventing IL22 from binding to the functional membrane-associated IL22 receptor (Xu et al. 2001, de Moura et al. 2009). This may play a regulatory role in inflammation.
Interleukin-20 receptor A (IL20RA) binds to Interleukin receptor B (IL20RB) (Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014). This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
The classical model of JAK-STAT signaling suggests that phosphorylated Signal transducer and activator of transcription 3 (STAT3) translocates to the nucleus (Akira et al. 1994) where it binds DNA to mediate the effects of Interleukin-10 (IL10) on expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, with important consequences for their ability to activate and sustain immune and inflammatory responses. STAT3 is able to shuttle freely between the cytoplasm and the nucleus, independent of tyrosine phosphorylation (Liu et al. 2005, Li 2008, Reich 2013). Binding of unphosphorylated STAT3 to DNA has been reported (Nkansah et al. 2013). As it is not clear what triggers nuclear accumulation of STAT3 in response to IL10 this event is shown as an uncertain process. Moreover this traslocation after STAT3 dimerization could occur as a product of Interleukin-22 signaling (Lagos-Quintana et al. 2003, Sestito et al. 2011). This is a black box event because there are not details about other proteins involved in this traslocation to the nucleous.
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) dimerizes after dissociate from the interleukin-19 (IL19) receptor complex. According to the classical model, phosphorylated Signal transducer and activator of transcription (STAT) monomers associate in an active dimer form, which is stabilized by the reciprocal interactions between a phosphorylated tyrosine residue of one and the SH2 domain of the other monomer (Shuai et al. 1994). These dimers then translocate to the nucleus (Akira et al. 1994). Recently an increasing number of studies have demonstrated the existence of STAT dimers in unstimulated cell states, and the capability of STATs to exert biological functions independently of phosphorylation (Braunstein et al. 2003, Li et al. 2008, Santos & Costas-Pereira 2011). As phosphorylation of STATs is not unequivocally required for its subsequent translocation to the nucleus, this event is shown as an uncertain process. On the other hand interleukin-22 is also participating in this event. It is stimulated after Interleukin-22 binding with Interleukin-22 receptor (Interleukin-22 receptor subunit alpha 1 and Interleukin-10 receptor subunit beta) (Lagos-Quintana et al. 2003, Sestito et al. 2011). This event is inferred from other interleukin cascades where before translocation to the nucleous the transcription factor dimerizes. It is a black box event because there is not physical evidence that this dimerization occurs afterInterleukin-22 stimulus.
Temporal models suggest that binding of Interleukin-22 (IL22) to Interleukin-22 receptor subunit alpha 1 (IL22RA1) creates a surface that is bound by the extracellular region of Interleukin-10 receptor beta chain (IL10RB) (Li et al. 2004).
Interleukin-24 (IL24) binds to a heterodimeric receptor complex formed by Interleukin-20 Receptor subunit alpha (IL20RA) associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB).
This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
Interleukin-20 (IL20) binds a heterodimeric receptor complex formed by Interleukin-20 Receptor subunit alpha (IL20RA) associated with Tyrosine-protein kinase JAK1 (JAK1) and Interleukin-20 receptor subunit beta (IL20RB). Interleukin-20 receptor A (IL20RA) and Interleukin-20 receptor B(IL20RB) form a receptor complex for Interleukin-19 (IL19) (and also Interleukin-20 (IL20) and Interleukin-24 (IL24)) (Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014). This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
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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.
Interleukin-20 receptor A (IL20RA) and Interleukin-20 receptor B (IL20RB) form a receptor complex for Interleukin-19 (IL19) (and also Interleukin-20 (IL20) and Interleukin-24 (IL24)) (Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014, Pletnev et al. 2003).
This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.
STAT3 is able to shuttle freely between the cytoplasm and the nucleus, independent of tyrosine phosphorylation (Liu et al. 2005, Li 2008, Reich 2013). Binding of unphosphorylated STAT3 to DNA has been reported (Nkansah et al. 2013). As it is not clear what triggers nuclear accumulation of STAT3 in response to IL10 this event is shown as an uncertain process.
Moreover this traslocation after STAT3 dimerization could occur as a product of Interleukin-22 signaling (Lagos-Quintana et al. 2003, Sestito et al. 2011).
This is a black box event because there are not details about other proteins involved in this traslocation to the nucleous.
According to the classical model, phosphorylated Signal transducer and activator of transcription (STAT) monomers associate in an active dimer form, which is stabilized by the reciprocal interactions between a phosphorylated tyrosine residue of one and the SH2 domain of the other monomer (Shuai et al. 1994). These dimers then translocate to the nucleus (Akira et al. 1994). Recently an increasing number of studies have demonstrated the existence of STAT dimers in unstimulated cell states, and the capability of STATs to exert biological functions independently of phosphorylation (Braunstein et al. 2003, Li et al. 2008, Santos & Costas-Pereira 2011). As phosphorylation of STATs is not unequivocally required for its subsequent translocation to the nucleus, this event is shown as an uncertain process.
On the other hand interleukin-22 is also participating in this event. It is stimulated after Interleukin-22 binding with Interleukin-22 receptor (Interleukin-22 receptor subunit alpha 1 and Interleukin-10 receptor subunit beta) (Lagos-Quintana et al. 2003, Sestito et al. 2011).
This event is inferred from other interleukin cascades where before translocation to the nucleous the transcription factor dimerizes.
It is a black box event because there is not physical evidence that this dimerization occurs afterInterleukin-22 stimulus.
Interleukin-20 receptor A (IL20RA) and Interleukin-20 receptor B(IL20RB) form a receptor complex for Interleukin-19 (IL19) (and also Interleukin-20 (IL20) and Interleukin-24 (IL24)) (Blumberg et al. 2001, Parrish-Novak et al. 2002, Logsdon et al. 2012, Rutz et al. 2014).
This is a black box event because it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as an uncertain event.