Immune response IL-4 signaling pathway
IL-4 signaling pathway
Interleukin-4 ( IL-4 ) is a T cell derived multifunctional cytokine that playsa critical role in the regulation of immune responses. IL-4 induces Th2 (T helper2) differentiation, causes macrophage suppression, and stimulates B cell production ofImmunoglobulins E, G1 and G4 ( IgE, IgG1 and IgG4 ) [1], [2], [3], [4], [5], [6], [7], [8], [9].
IL-4 can stimulate two receptors, type I and type II. IL-4 receptor type I (IL-4R type I ) consists of two subunits, an alpha chain ( IL4RA ) and acommon gamma chain, shared by other cytokines of the IL-2 family [10], [11].
IL-4 binding to IL-4R type I activates several different pathwaysfollowed by B cell proliferation, survival of T and B cells, and the production ofchemokines important for the recruitment of cells that participate in allergic immuneresponses [4], [12].
IL-4 engagement of IL-4R type I results in tyrosine phosphorylation ofJanus kinases 1 and 3 ( JAK1 and JAK3 ) [13], [14],[15]. JAK1 phosphorylates Signal transducer and activator oftranscription 6 ( STAT6 ), which dimerizes and is translocated to the nucleus[16], [17], [18], [19], [9].In the nucleus, STAT6 promotes transcription of target genes, including Suppressorof cytokine signaling 1 ( SOCS1 ), IL4RA, Chemokine (C-C motif) ligand 11( Eotaxin ), GATA binding protein 3 ( GATA-3 ), Fc fragment of IgE, lowaffinity II, receptor for ( CD23 ), Immunoglobulin heavy constant epsilon (IGHE ), Immunoglobulin heavy constant gamma 1 ( IGHG1 ) and Immunoglobulinheavy constant gamma 4 ( IGHG4 ) [16], [20], [21], [22], [23], [24], [25], [2], [26], [27], [28], [29].
Interaction of SOCS1 with JAK1, and association of Suppressor ofcytokine signaling 5 ( SOCS5 ) with IL-4R type I result in the inhibitionof IL-4 -mediated STAT6 activation [30], [31],[32].
In response to IL-4 signaling, JAK1 phosphorylates Inositolpolyphosphate-5-phosphatase 145kDa ( SHIP ) followed by positive regulation ofcell proliferation [33], [30].
JAK1 and JAK3 also phosphorylate two adapter molecules, Insulin receptorsubstrate 1 and 2 ( IRS-1 and IRS-2 ), leading to the activation ofPhosphatidylinositol 3-kinase (PI3K) and Mitogen-activated protein (MAP) pathways [34], [35].
Phosphorylated IRS-1 and IRS-2 bind to and activate the PI3K regulatorysubunit ( PI3K reg class IA ), which stimulates the PI3K catalytic subunit (PI3K cat class IA ), generating Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3 ) from Phosphatidylinositol-4,5-bisphosphate ( PtdIns(4,5)P2 ). PtdIns(3,4,5)P3 activates 3-Phosphoinositide dependent proteinkinase-1 ( PDK (PDPK1) ) and v-Akt murine thymoma viral oncogene homolog (AKT(PKB) ) [36], [37], [18], [38],[39].
Association of Feline sarcoma oncogene ( c-Fes ) with IL-4R type I andwith PI3K reg class IA upon IL-4 stimulation can also induce PI3Kactivation [40], [41], [42].
The downstream effectors of PI3K cat class IA/ PDK (PDPK1) andAKT(PKB) signaling, such as Ribosomal protein S6 kinase 70kDa polypeptide 1 (p70S6K ), FK506 binding protein 12-rapamycin associated protein 1 ( mTOR )and Glycogen synthase kinase 3 beta ( GSK3 beta ), mediate the effect of PI3K oncell survival by preventing apoptosis and stimulating cell growth and proliferation[43], [44], [39], [45], [46].
AKT also stimulates Nuclear factor-kappa B ( NF-kB ) activity byupregulating I-kappaB ( I-kB ) degradation via phosphorylation of I-kappaB kinasealpha ( IKK-alpha ), a subunit of I-kappaB kinase complex ( IKK (cat) ),thereby allowing the transcription of NF-kB target genes [47], [48].
IRS-1 and IRS-2 also activate Growth factor receptor-bound protein 2 (GRB2 ), followed by stimulation of the MAP pathway: GRB2/ Son of sevenlesshomologs ( SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras )/ v-Raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/Extracellular signal-regulated kinase 1 and 2 ( ERK1/2 ). This pathway inducesactivation of transcription factors, including ELK1 member of ETS oncogene family (Elk-1 ) [49], [50], [37], [51],[52], [19].
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