Immune response - IL-4 signaling pathway

IL-4 signaling pathway

Interleukin-4 (IL-4) is a T cell derived multifunctional cytokine that plays a critical role in the regulation of immune responses. IL-4 induces Th2 (T helper 2) differentiation, causes macrophage suppression, and stimulates B cell production of Immunoglobulins 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 a common gamma chain, shared by other cytokines of the IL-2 family [10], [11].

IL-4 binding to IL-4R type I activates several different pathways followed by B cell proliferation, survival of T and B cells, and the production of chemokines important for the recruitment of cells that participate in allergic immune responses [4], [12].

IL-4 engagement of IL-4R type I results in tyrosine phosphorylation of Janus kinases 1 and 3 (JAK1 and JAK3) [13], [14], [15]. JAK1 phosphorylates Signal transducer and activator of transcription 6 (STAT6), which dimerizes and is translocated to the nucleus [9], [16], [17], [18], [19]. In the nucleus, STAT6 promotes transcription of target genes, including Suppressor of cytokine signaling 1 (SOCS1), IL4RA, Chemokine (C-C motif) ligand 11 (Eotaxin), GATA binding protein 3 (GATA-3), Fc fragment of IgE, low affinity II, receptor for (CD23), Immunoglobulin heavy constant epsilon (IGHE), Immunoglobulin heavy constant gamma 1 (IGHG1) and Immunoglobulin heavy constant gamma 4 (IGHG4) [2], [16], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29].

Interaction of SOCS1 with JAK1, and association of Suppressor of cytokine signaling 5 (SOCS5) with IL-4R type I result in the inhibition of IL-4-mediated STAT6 activation [30], [31], [32].

In response to IL-4 signaling, JAK1 phosphorylates Inositol polyphosphate-5-phosphatase 145kDa (SHIP) followed by positive regulation of cell proliferation [30], [33].

JAK1 and JAK3 also phosphorylate two adapter molecules, Insulin receptor substrate 1 and 2 (IRS-1 and IRS-2), leading to the activation of Phosphatidylinositol 3-kinase (PI3K) and Mitogen-activated protein (MAP) pathways [34], [35].

Phosphorylated IRS-1 and IRS-2 bind to and activate the PI3K regulatory subunit (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 protein kinase-1 (PDK (PDPK1)) and v-Akt murine thymoma viral oncogene homolog (AKT(PKB)) [18], [36], [37], [38], [39].

Association of Feline sarcoma oncogene (c-Fes) with IL-4R type I and with PI3K reg class IA upon IL-4 stimulation can also induce PI3K activation [40], [41], [42].

The downstream effectors of PI3K cat class IA/ PDK (PDPK1) and AKT(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 on cell survival by preventing apoptosis and stimulating cell growth and proliferation [39], [43], [44], [45], [46].

AKT also stimulates Nuclear factor-kappa B (NF-kB) activity by upregulating I-kappaB (I-kB) degradation via phosphorylation of I-kappaB kinase alpha (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 sevenless homologs (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 induces activation of transcription factors, including ELK1 member of ETS oncogene family (Elk-1) [19], [37], [49], [50], [51], [52].

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