Interleukin-4 and Interleukin-13 signaling (Homo sapiens)

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26, 369, 726, 7, 17, 28, 32...27, 29, 8638552, 70, 88853838417732, 47, 58, 62, 71...41, 56414, 25, 33, 41, 42779613, 8837, 41, 7741, 778923, 6122, 3512, 46, 57, 6839610, 90118121, 24, 30, 32, 34...1445, 4911571, 8, 16, 18, 19, 32...3, 15, 762, 41398120, 88413831, 3823, 46, 61, 67, 824131, 38cytosolmitochondrial matrixnucleoplasmendoplasmic reticulum lumenHSPA8 MMP2(110-660) IL13-boundtyrosine-phosphorylated IL13 receptor type II with phosphorylated STAT1,STAT3,STAT6TYK2 RORC gene TNFRSF1B TYK2 p-Y1007-JAK2 IL18 gene STAT3-upregulatednuclear proteinsp-Y701-STAT1 ATPJAK1 RHOU gene NDN ADPADPp-Y641-STAT6 FOXO3 IL4 JAK1 p-Y-IL4R FCER2(1-321) IL4R STAT1 gene p-Y705-STAT3 LIF SOCS1 geneIL4BCL6 gene IL13 p-Y705-STAT3 TYK2 FGF2(10-155) STAT3-upregulatedplasma membraneproteinsVEGFA HIF1A BCL2 gene, BCL2L1genep-Y705-STAT3 dimer,p-Y641-STAT6 dimerp-Y641-STAT6 STAT6 p-Y641-STAT6 IL4 IL4R IL1B IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:p-Y705-STAT3,p-Y641-STAT6p-Y705-STAT3 JAK2 ITGAM ANXA1 SOCS5 SOX2 p-Y705-STAT3,p-Y641-STAT6VEGFA gene IL13-downregulatedgenes forextracellularproteinsRORC STAT3-upregulatedgenes for plasmamembrane proteinsIL2RG JAK2 COL1A2 gene IL10 gene IGHE gene BCL2 ANXA1 gene JUNB gene IL12B gene IL6 gene SOCS3 gene IL13:IL13RA:TYK2p-Y701-STAT1 p-Y705-STAT3 TIMP1 PIM1 ZEB1 p-Y641-STAT6 POMC(138-176) ALOX5 gene IL23A gene NOS2 gene p-Y-IL4R JAK3LAMA5 gene IL13RA1ADPTWIST1 p-Y641-STAT6 HGF gene IL17A STAT3-upregulatedextracellularproteinsIL17F S1PR1 IL13-boundtyrosine-phosphorylated IL13R type IIBCL2L1 SOCS3 JAK3 MMP1(84-469) TWIST1 gene IL6R gene MMP1 gene MYC JAK2 POMC gene CCND1 gene VIM p-Y641-STAT6 IL13-upregulatedgenes for plasmamembrane proteinsIL8 gene IL13RA1 STAT3,STAT6TNF(77-233) MAOAIL17A gene IL8 TGFB1 gene IL1A gene Bcl-2/Bcl-X(L)IRF4 HSP90AA1 gene CCL22 gene IL4:IL4R:JAK2:IL13RA1:TYK2p-Y705-STAT3 IL4:IL4R:JAK2:IL13RA:TYK2:SOCS5,(SOCS1)AKT1 gene IL4R JAK1 FOXO1 gene IL4R MUC1 gene CCND1 IL18(1-193) CEBPD p-Y701-STAT1dimer,p-Y705-STAT3dimer,p-Y641-STAT6dimerSTAT3-upregulatedcytosolic proteinsMCL1 gene JAK2 ATPIL4R gene CCL2 JAK2 STAT3-upregulatedgenes forextracellularproteinsGATA3IL13RA1 IL13RA2IL4 IL4 FOXO3 gene STAT6 IL13:IL13RA:TYK2:IL4R:JAK2:JAK1TYK2 p-Y-IL4R TP53 p-Y701-STAT1dimer,p-Y705-STAT3dimer,p-Y641-STAT6dimerMMP9 gene IL18, ALOX5IL13IL13 TNFRSF1B gene ATPIL4,IL13-downregulated extracellular proteinsIL6 FCER2 gene IL6R SOX2 gene MCL1 IGHE FOS gene IL13 IL4RSTAT3 IL4 IL4 VIM gene IL2RG IL4R JAK2BIRC5 gene MMP9 S1PR1 gene TP53 gene JAK3 FSCN1 FSCN1 gene IL13RA2 PTGS2STAT1 SOCS1CCL22(25-93) SOCS1 NDN gene, TP53 geneIL4, IL13STAT1 MYC gene IL1B gene IGHG1 gene STAT6 upregulatedextracellularprotein genesNOS2 IL13-upregulatedproteinsRORA gene OPRM1 IL4,IL13-downregulated genes for extracellular proteinsIL13RA1:TYK2p-Y701-STAT1 FASLG(1-281)JAK2 BIRC5 ALOX15 IL13RA1 STAT6 upregulatedextracellularproteinsp-Y-IL13RA1 OSM HSP90AA1 PIM1 gene AKT1 IL1B gene IL6 NANOG TYK2 STAT3 IGHG4 gene HIF1A gene IL12A gene ITGB1 MMP3(100-477) STAT3 IL12A IL4R p-Y705-STAT3 dimerLIF gene p-Y705-STAT3 IL4,IL13-upregulatedextracellularproteinsp-Y-IL4R STAT3 SAA1(19-122) IL10 HGF(32-494) CCL11 gene IL4,IL13-upregulatedextracellular genesBCL6 CDKN1A gene RHOU p-Y1007-JAK2 ITGB2 PIK3R1 OPRM1 gene JAK1IL4:IL4R:JAK2:IL2RG:JAK3:JAK1IL13 SOCS5,(SOCS1)NDN, TP53OPRD1 gene HSPA8 gene, ALOX15geneJAK3 TNF gene IL23R IL1A gene p-Y641-STAT6 OPRD1 p-Y705-STAT3 dimer,p-Y614-STAT6 dimerJUNB TYK2IL4R p-Y-IL13RA1 F13A1 gene IL13-boundtyrosine-phosphorylated IL13 receptor type II with STAT1,STAT3,STAT6ITGAM gene MAOA geneHSPA8 gene p-Y-IL2RG IGHG1 JAK1 IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:STAT3,STAT6JAK2 PIK3R1 gene CEBPD gene IL18 gene, ALOX5geneHMOX1JAK3 IL23R gene STAT6 IL4:IL4R:JAK2p-Y-IL2RG POU2F1 STAT6 IL6 gene BATF TYK2 TNF(77-233) STAT3-upregulatedgenes for cytosolicproteinsLBP ALOX5 FCER2(1-321) FN1(32-2386) HSP90B1FCER2 gene ALOX15 gene LCN2 gene IL4 p-Y-TYK2 ICAM1 gene IL2RG:JAK3CDKN1A MUC1(24-1255) FOS BCL2 gene IL2RG p-Y-TYK2 IL13RA1 MMP3 gene p-Y-JAK1 p-Y-IL13RA1 IL13:IL13RA:TYK2:IL4R:JAK2IL4R IL17F gene p-Y641-STAT6 CD36 geneIL13 IL13-downregulatedproteinsSOCS5 ATPIL1B,Myr82K-Myr83K-IL1A CCL2 gene MMP2 gene IL4R IL13RA1 p-Y701-STAT1 IL13BATF gene NANOG gene IL4 p-Y-IL4R JAK2 JAK2 STAT6 upregulatedplasma membraneprotein genesOSM gene FN1 gene p-Y-IL2RG HMOX1 geneTIMP1 gene p-Y701-STAT1,p-Y705-STAT3,p-Y641-STAT6JAK2 p-Y1007-JAK2 IL13 IL13:IL13RA2IGHG4 SOCS1 LAMA5 IL12B IRF4 gene POU2F1 gene p-Y641-STAT6 IL2RGIL4:IL4R:JAK2:IL2RG:JAK3IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1ITGAX VCAM1 p-Y705-STAT3 JAK2 TNF gene Myr82K-Myr83K-IL1A STAT1 ZEB1 gene IL23A ICAM1 HSPA8, ALOX15JAK3 p-Y705-STAT3 IL13RA1 p-Y-TYK2 CCL11 GATA3 geneLBP gene IL13 factor XIII A chain 4xPalmC-CD36FOXO1 SAA1 gene COL1A2 JAK1 VCAM1 gene STAT6 upregulatedplasma membraneproteinsIL4R:JAK2ADPSTAT3-upregulatedgenes for nuclearproteinsp-Y-JAK1 TGFB1(30-278) PTGS2 geneITGAX gene p-Y-IL4R FGF2 gene NDN gene IL4 STAT1,STAT3,STAT6IL13 JAK3 ITGB1 Gene RORA BCL2L1 gene LCN2 ITGB2 gene p-Y641-STAT6 dimerp-Y705-STAT3 FASLG genep-Y-JAK1 7473


Interleukin-4 (IL4) is a principal regulatory cytokine during the immune response, crucially important in allergy and asthma (Nelms et al. 1999). When resting T cells are antigen-activated and expand in response to Interleukin-2 (IL2), they can differentiate as Type 1 (Th1) or Type 2 (Th2) T helper cells. The outcome is influenced by IL4. Th2 cells secrete IL4, which both stimulates Th2 in an autocrine fashion and acts as a potent B cell growth factor to promote humoral immunity (Nelms et al. 1999).

Interleukin-13 (IL13) is an immunoregulatory cytokine secreted predominantly by activated Th2 cells. It is a key mediator in the pathogenesis of allergic inflammation. IL13 shares many functional properties with IL4, stemming from the fact that they share a common receptor subunit. IL13 receptors are expressed on human B cells, basophils, eosinophils, mast cells, endothelial cells, fibroblasts, monocytes, macrophages, respiratory epithelial cells, and smooth muscle cells, but unlike IL4, not T cells. Thus IL13 does not appear to be important in the initial differentiation of CD4 T cells into Th2 cells, rather it is important in the effector phase of allergic inflammation (Hershey et al. 2003).

IL4 and IL13 induce “alternative activation� of macrophages, inducing an anti-inflammatory phenotype by signaling through IL4R alpha in a STAT6 dependent manner. This signaling plays an important role in the Th2 response, mediating anti-parasitic effects and aiding wound healing (Gordon & Martinez 2010, Loke et al. 2002)

There are two types of IL4 receptor complex (Andrews et al. 2006). Type I IL4R (IL4R1) is predominantly expressed on the surface of hematopoietic cells and consists of IL4R and IL2RG, the common gamma chain. Type II IL4R (IL4R2) is predominantly expressed on the surface of nonhematopoietic cells, it consists of IL4R and IL13RA1 and is also the type II receptor for IL13. (Obiri et al. 1995, Aman et al. 1996, Hilton et al. 1996, Miloux et al. 1997, Zhang et al. 1997). The second receptor for IL13 consists of IL4R and Interleukin-13 receptor alpha 2 (IL13RA2), sometimes called Interleukin-13 binding protein (IL13BP). It has a high affinity receptor for IL13 (Kd = 250 pmol/L) but is not sufficient to render cells responsive to IL13, even in the presence of IL4R (Donaldson et al. 1998). It is reported to exist in soluble form (Zhang et al. 1997) and when overexpressed reduces JAK-STAT signaling (Kawakami et al. 2001). It's function may be to prevent IL13 signalling via the functional IL4R:IL13RA1 receptor. IL13RA2 is overexpressed and enhances cell invasion in some human cancers (Joshi & Puri 2012).

The first step in the formation of IL4R1 (IL4:IL4R:IL2RB) is the binding of IL4 with IL4R (Hoffman et al. 1995, Shen et al. 1996, Hage et al. 1999). This is also the first step in formation of IL4R2 (IL4:IL4R:IL13RA1). After the initial binding of IL4 and IL4R, IL2RB binds (LaPorte et al. 2008), to form IL4R1. Alternatively, IL13RA1 binds, forming IL4R2. In contrast, the type II IL13 complex (IL13R2) forms with IL13 first binding to IL13RA1 followed by recruitment of IL4R (Wang et al. 2009).

Crystal structures of the IL4:IL4R:IL2RG, IL4:IL4R:IL13RA1 and IL13:IL4R:IL13RA1 complexes have been determined (LaPorte et al. 2008). Consistent with these structures, in monocytes IL4R is tyrosine phosphorylated in response to both IL4 and IL13 (Roy et al. 2002, Gordon & Martinez 2010) while IL13RA1 phosphorylation is induced only by IL13 (Roy et al. 2002, LaPorte et al. 2008) and IL2RG phosphorylation is induced only by IL4 (Roy et al. 2002).

Both IL4 receptor complexes signal through Jak/STAT cascades. IL4R is constitutively-associated with JAK2 (Roy et al. 2002) and associates with JAK1 following binding of IL4 (Yin et al. 1994) or IL13 (Roy et al. 2002). IL2RG constitutively associates with JAK3 (Boussiotis et al. 1994, Russell et al. 1994). IL13RA1 constitutively associates with TYK2 (Umeshita-Suyama et al. 2000, Roy et al. 2002, LaPorte et al. 2008, Bhattacharjee et al. 2013).

IL4 binding to IL4R1 leads to phosphorylation of JAK1 (but not JAK2) and STAT6 activation (Takeda et al. 1994, Ratthe et al. 2007, Bhattacharjee et al. 2013).

IL13 binding increases activating tyrosine-99 phosphorylation of IL13RA1 but not that of IL2RG. IL4 binding to IL2RG leads to its tyrosine phosphorylation (Roy et al. 2002). IL13 binding to IL4R2 leads to TYK2 and JAK2 (but not JAK1) phosphorylation (Roy & Cathcart 1998, Roy et al. 2002).

Phosphorylated TYK2 binds and phosphorylates STAT6 and possibly STAT1 (Bhattacharjee et al. 2013).

A second mechanism of signal transduction activated by IL4 and IL13 leads to the insulin receptor substrate (IRS) family (Kelly-Welch et al. 2003). IL4R1 associates with insulin receptor substrate 2 and activates the PI3K/Akt and Ras/MEK/Erk pathways involved in cell proliferation, survival and translational control. IL4R2 does not associate with insulin receptor substrate 2 and consequently the PI3K/Akt and Ras/MEK/Erk pathways are not activated (Busch-Dienstfertig & González-Rodríguez 2013).

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