Disease relevance of IL4R

• To evaluate antitumor activity, nude mice carrying s.c. tumors composed of IL4R-bearing human A431 epidermoid carcinoma cells were injected with recombinant toxins i.v. every other day for three doses [1].
• IL4(38-37)-PE38KDEL and IL4-PE38KDEL exhibited similar toxicity and pharmacokinetics in the mice, indicating that the improved antitumor activity of the circularly permuted IL4-toxin was due to its improved binding to the IL4R on the target cells [1].
• We have targeted IL4R on a human solid tumor xenograft with chimeric proteins composed of human IL4 (hIL4) and 2 different mutant forms of a powerful bacterial toxin, Pseudomonas exotoxin A (PE) [2].
• The observation that IL-2R gamma is a functional component of the IL-4 receptor, together with the finding that IL-2R gamma associates with the IL-7 receptor, begins to elucidate why deficiency of this common gamma chain (gamma c) has a profound effect on lymphoid function and development, as seen in X-linked severe combined immunodeficiency [3].
• Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin [4].

High impact information on IL4R

• Its effects depend upon binding to and signaling through a receptor complex consisting of the IL-4R alpha chain and the common gamma chain (gamma c), resulting in a series of phosphorylation events mediated by receptor-associated kinases [5].
• Punctate methylation patterns are also evident at the cytokine and IL-4 receptor loci [6].
• Atopy and a mutation in the interleukin-4 receptor gene [7].
• IL-4 binds with high affinity and specificity to the ectodomain of the IL-4 receptor alpha chain (IL4-BP) [8].
• The interleukin-4 receptor variant Q576R in hyper-IgE syndrome [9].

Chemical compound and disease context of IL4R

• Kay and co-workers in this issue of Leukemia Research have targeted interleukin-4 receptors (IL4R) on CLL B cells with a recombinant IL4 pseudomonas exotoxin fusion protein (IL-4(38--37)-PE38KDEL) [10].
• The fall in serum IL-4 seen during the grass pollen season in the hayfever patients may reflect allergen driven upregulation of membrane IL-4 receptor expression or sequestration of cytokine producing cells to inflammatory sites [11].
• We have utilized a mouse model of the Bernard-Soulier syndrome to engineer platelets expressing an alpha-subunit of GP Ib (GP Ibalpha) in which most of the extracytoplasmic sequence has been replaced by an isolated domain of the alpha-subunit of the human interleukin-4 receptor (IL-4Ralpha) [12].

Biological context of IL4R

• Here, we studied the signal transduction events following IL4R activation and leading to CD23 expression on resting B cells [13].
• We demonstrate that IL4R triggering induced the tyrosine phosphorylation of JAK3 and of a p170 protein [13].
• Our findings indicate that the Ile50Val polymorphism of IL4R does not play a substantial role in genetic predisposition for the etiology of atopy or asthma in this Japanese population [14].
• We analyzed the 5' promoter region of the human IL4R alpha-chain gene (IL4RA) of healthy volunteers by DNA sequencing and found three novel single-nucleotide polymorphisms (SNPs; T-890C, T-1914C, C-3223T) and one novel short tandem repeat [(CAAAA)(5-7)-3600] [15].
• By considering the probands and their spouses as an unrelated sample, we observed significant associations of atopy and asthma-related phenotypes with several IL4RA polymorphisms, including S478P and total serum IgE levels (P=.0007) [16].

Anatomical context of IL4R

• CONCLUSION: Chondrocytes from normal and OA cartilage signal through a Type II IL4R [17].
• Reactivity of normal brain endothelium was observed for TfR, and reactivity of normal brain astrocytes was observed for IL4R [18].
• The glioblastoma-derived cell lines T98G, GRE, and M007, which do not express the IL-4Ralpha chain, fail to support Stat6 activation in response to either IL-4 or PV [19].
• Endothelial cell bound both cytokines with high affinity; by flow cytofluorometry and reverse transcription-polymerase chain reaction (RT-PCR), they expressed IL-4 receptor alpha (IL-4R alpha) but did not express the gamma c of the IL-2R [20].
• In the T cell line CTLL2, ligation of kit/IL-4R alpha induces cellular proliferation [21].

Associations of IL4R with chemical compounds

• Differences in IL4 signalling are likely due to crosstalk between integrin and cytokine signalling pathways, and not differences in IL4R expression [17].
• Activation of STAT6 is not dependent on phosphotyrosine-mediated docking to the interleukin-4 receptor and can be blocked by dominant-negative mutants of both receptor subunits [22].
• DNA was extracted from blood collected in EDTA tubes, and polymorphisms at positions 50 and 551 of the IL4 receptor, position 110 of IL13 and position 181 of the high-affinity IgE receptor were investigated by sequence-specific PCR or direct sequencing [23].
• However, activation of Ca(2+)-dependent pathways with A23187 or stimulation with IL-4 had no effect on the IL-4R expression [24].
• Activation of protein kinase C-dependent pathways with phorbol myristate acetate (PMA) or activation of protein kinase A-dependent pathways with DBcAMP and prostaglandin E2 resulted in an augmented IL-4R expression at mRNA and protein level [24].

Physical interactions of IL4R

• Unlabeled IL-13 competed successfully for IL-4 binding at 65 to 75 kD but was unable to completely displace Il-4 from its binding to the IL-4R alpha [20].
• Through a deletion analysis of the IL-4R we have identified a putative FES-binding site in the cytoplasmic domain of the IL-4R [25].
• RESULTS: SHP-2 bound IL-4Ralpha synthetic peptide; this binding was reduced in the presence of the R551 variant [26].
• Co-expression of the cloned cDNA with that of IL-4R alpha resulted in a receptor complex that displayed high affinity for IL-13 (Kd approximately 30 pM), and that allowed cross-competition of IL-13 and IL-4 [27].
• Changes in the NMR-derived motional parameters of the insulin receptor substrate 1 phosphotyrosine binding domain upon binding to an interleukin 4 receptor phosphopeptide [28].

Enzymatic interactions of IL4R

• Mechanical stimulation (MS) resulted in an IL4R-dependent increase in phosphorylated Tyk2 in normal chondrocytes, which could be abolished by IL1beta preincubation [17].
• We present the NMR structure of the PTB domain of insulin receptor substrate-1 (IRS-1) complexed to a tyrosine-phosphorylated peptide derived from the IL-4 receptor [29].

Regulatory relationships of IL4R

• Both interleukin 4 and interleukin 13 induce tyrosine phosphorylation of the 140-kDa subunit of the interleukin 4 receptor [30].
• Recently we reported a correlation between the ability of IL-4 to regulate TNFalpha production by monocytes and the expression of the IL-4 receptor gamma chain or gamma common (gamma c chain) [31].
• Stimulation of cells with IL-2 and IL-7 induced identical phosphorylation patterns to each other but not phosphorylation of the 140-kDa IL-4 receptor subunit [30].
• Exposure to EGF for 24 h enhanced IL-4R alpha mRNA levels; in contrast, IL-4 yielded no increase [32].
• Both IL-4 and IL-2 induced upregulation of IL-4R on activated normal T cells but not on ATL cells [33].

Other interactions of IL4R

• Murine L929 cells, which do not express the gamma common chain of the IL-4 receptor, support PV-mediated but not IL-4-dependent Stat6 activation [19].
• A significant gene-gene interaction between S478P in IL4RA and the -1111 promoter variation in IL13, previously shown to be associated with BHR (P=.003), was detected [16].
• Thus, Stat6 activation by PV is an IL-4Ralpha-mediated, Jak1-dependent event that is independent of receptor dimerization [19].
• JAK3 associates with the human interleukin 4 receptor and is tyrosine phosphorylated following receptor triggering [13].
• We have found that CD40-mediated signals cause a fivefold upregulation of IL-4 receptor (IL-4R) on the B cell surface and that this is associated with a 100-1000-fold increase in the cells' responsiveness to the cytokine [34].

Analytical, diagnostic and therapeutic context of IL4R

• METHODS: Expression of IL4R subunits and associated molecules was assessed by immunohistochemistry and western blotting [17].
• Functional IL4R were identified by chemical crosslinking of IL4-stimulated chondrocytes and western blotting [17].
• Radioligand cross-linking experiments followed by immunoprecipitation with the monoclonal antibody (MoAb) S697 to the IL-4R alpha showed IL-4-specific binding at 130 kD, the IL-4R alpha, and to a minor extent to a double band coimmunoprecipitated at 65 to 75 kD [20].
• Molecular cloning of a cDNA encoding the human interleukin 4 receptor [35].
• Detection of and discrimination between total and free human interleukin-4 and free soluble interleukin-4 receptor by ELISA [36].

References