IL4 Pathway

IL4 is a multifunctional cytokine produced by TH2 type helper T cells, fibroblasts, mast cells, basophils, eosinophils, adipose, and a wide range of epithelial cells. IL4 acts on a broad range of cells, including keratinocytes, in which it induces IL6 production.   IL4 cognate receptors are of two types: I IL4R (IL4RI) and type II IL4R (IL4RII). IL4RI are mostly present on immune cells and forms heterodimer with the common gamma-chain subunits. IL4RII on the other hand is found on the surface of non-hematopoietic cells and is composed of IL4Ralpha and the IL13Ralpha1 subunits. IL4 activates tyrosine kinases JAK1/3 and TYK2, which are recruited on the transmembrane domain of IL4RII and mediate its phosphorylation, leading to the activation of PI3K/AKT, MAPK, and JAK/STAT6 downstream pathways (Ref.1).

 

 

STAT6, along with IRS2 is the major pathway involved in IL4 signaling, although STAT3 and other STATs are also believed to be activated in some cell types. STAT6 tyrosine phosphorylation leads to STAT6 homodimerization. STAT6 dimer then translocates to the nucleus and is involved in gene transcription. IRS2 activation generally activates PI3K, AKT and NF-kappaB-driven gene transcription, and plays an important role in cell cycle, cell proliferation and survival (Ref.2). IL4R signaling is also mediated by SHC/ERK1/2 (MAPK)-dependent pathways.  IL4 receptor signaling is less dependent upon the SHC-MAPK pathway and mainly mediated by the JAK/STAT and PI3K/AKT pathways (Ref.3).

 

Tyrosine phosphorylation of sites within both IRS1 and IRS2 allows their high affinity association with cellular proteins that contain SH2 domains including GRB2 (Growth-Factor Receptor-Bound Protein-2), and the SHP2 (Src-Homology Protein Tyrosine Phosphatase-2), as well as other signaling molecules. GRB2 is constitutively complexed to the guanine nucleotide exchange protein SOS (Son of Sevenless). The primary function of SOS is to catalyze the exchange of GDP in inactive RAS for GTP, producing the active GTP-bound form of RAS. The MAPK (Mitogen-Activated Protein Kinases) pathway is initiated by the Ser/Thr kinase RAF following its activation by RAS-GTP. Active RAF initiates a cascade of kinase activation events that ultimately result in the phosphorylation and activation of the MAPK ERK1/2 (Extracellular Signal Regulated Kinase). Active ERK1/2 translocates to the nucleus and activates the expression of genes such as c-FOS by phosphorylating specific transactivating factors (Ref.4). Besides ERK, IL4 may also be involved in the activation of other MAPKs like p38 and JNK. Studies have reported the critical role of p38 MAPK in IL4-induced macrophage polarization. Under stress conditions, in tumor cells IL4 is believed to activate JNK-pathway, leading to the further activation of transcription factor c-Myc. MAPKs activated by IL4 are important for cellular processes like proliferation, differentiation, activation and survival of immune cells (Ref.5).  IL4 is a key cytokine capable of inducing the differentiation of Th2 lymphocytes, B-cell proliferation and class switching. It helps in sustaining the allergic responses like asthma. Drugs targeting IL4 receptor and blocking their signaling can be effective in treating asthma (Ref.6). IL4 have been important in regulating immune responses and are found at high levels in cancer patients. However, its role in therapy resistance has not yet been determined. IL4 may contribute to cancer relapse by providing a niche favourable for the growth of certain cancer stem cells (Ref.7).