Ligand Description

Ligand name: Interleukin 4

3-Letter code: I04

Ligand screen reagent: Interleukin-4, recombinant mouse, baculovirus-infected insect cells (IL-4)

Protocol: PL00000004

Description of ligand: Interleukin 4 (IL-4; AfCS ID A001262) is a pleiotropic type I cytokine expressed by Th2 T lymphocytes (T cells), basophils, and mast cells. IL-4 may also be secreted by NK T cells, gamma/delta T cells, and eosinophils under some circumstances. Like other type I cytokines, its tertiary structure is defined by a hydrophobic core consisting of 4 alpha helices. The hydrophobic core of IL-4 is very similar to that of IL-13. IL-4 and IL-13 share many functions.

Receptor: IL-4 has been found to bind to two different receptors. The type I receptor is a heterodimer composed of the 140-kDa IL-4 receptor alpha chain (IL-4Ralpha, CD124; AfCS ID A001263) and the 65- to 70-kDa common gamma chain (CD132, A000533). The membrane-bound form of IL-4Ralpha is 140 kDa and binds to IL-4 with a Kd of 20 to 300 pM. A 40 kDa soluble form has been found generated as a result of alternative splicing. The common gamma chain is an essential component of the receptors for several cytokines, including IL-2, IL-4, IL-7, IL-9, and IL-15. The type II receptor is a heterodimer composed of the IL-4Ralpha chain and the IL-13 receptor alpha chain (A001250/A001251).

Membrane-proximal signaling events: Heterodimerization or multimerization of the IL-4 receptor results in the phosphorylation and activation of the protein tyrosine kinases, Janus kinase (JAK) 1 (A001290) and JAK3 (A001292). The type II receptor activates the JAK1 and Tyk2 tyrosine kinases. These kinases phosphorylate tyrosine residues in the cytoplasmic domain of the IL-4Ralpha chain, which can then act as binding sites for the insulin receptor substrate (IRS)-2 (A001282) adaptor protein and the signal transducer and activator of transcription (STAT) 6 (A002236) transcription factor.

Intracytoplasmic signaling events: Upon IL-4 binding, IRS-2 binds to the IL-4Ralpha chain and is tyrosine phosphorylated. This creates binding sites for PI 3-kinase (e.g., A001768/A001769). The recruitment of PI 3-kinase to the plasma membrane results in PI 3-kinase-dependent signaling events. Tyrosine phosphorylated IRS-2 can also recruit Grb2/SOS complexes and thereby promote ERK activation. The phosphatases SHP-1, SHP-2, and SHIP bind to a phosphotyrosine-containing ITIM sequence on the IL-4Ralpha chain and limit IL-4R signaling.

Transcription factor targets: Jak activation results in the phosphorylation of the IL-4Ralpha chain and recruitment and phosphorylation of STAT6. STAT6 phosphorylation results in dimerization of STAT6 and translocation of STAT6 into the nucleus, where it activates transcription of genes containing specific interferon-gamma-activated site (GAS)-like sequences.

Gene expression responses: IL-4 treatment of macrophages results in the increased transcription of the genes encoding CD23 (A000543), MHC class II proteins, IL-4 receptor alpha, arginase, IL-1 receptor antagonist (IL-1Ra), and the IL-1RII decoy receptor, the chemokines MDC (CCL22) and TARC (CCL17), and several members of the SOCS family (especially SOCS-3; A002188). SOCS proteins are suppressors of cytokine signaling and appear to function in a negative feedback loop to turn the signaling pathway off.

Cellular responses in B cells: IL-4 has been found to stimulate B cell proliferation, to support B cell survival in culture, and to induce B cell differentiation, including immunoglobulin class switching to the IgE and IgG1 (IgG4 for human) isotype.

Cellular responses in macrophages: IL-4 has been found to upregulate the expression of the mannose receptor as well as MHC class II molecules. This stimulates endocytosis of microbes and subsequent presentation of microbial antigens to T cells. IL-4 induces the expression of MDC (CCL22) and TARC (CCL17) chemokines that recruit TH2 type helper T cells. IL-4 also induces the expression of arginase, which inhibits nitric oxide production while enhancing collagen production. IL-4 causes modest suppression (compared to the much stronger suppression by IL-10) of the LPS-induced respiratory burst and LPS-induced production of inflammatory cytokines such as TNF-alpha. It also enhances the release of IL-1 receptor antagonist (IL-1Ra) and the soluble IL-1RII decoy receptor, both of which downregulate the pro-inflammatory effects of IL-1.

Note: IL-13 produces similar responses.

Example of IL-4 effects on RAW 264.7 cells and dose range: IL-4 (1-5 ng/ml) inhibits LPS-induced translation of TNF-alpha mRNA.

References:
Mijatovic T, Kruys V, Caput D, Defrance P, and Huez G. (1997) Interleukin-4 and -13 inhibit tumor necrosis factor-alpha mRNA translational activation in lipopolysaccharide-induced mouse macrophages. J. Biol. Chem. 272(22), 14394-14398.
Gessner A and Rollinghoff M. (2000) Biological functions and signaling of the interleukin-4 receptor complexes. Immunobiology 201(3-4), 285-307.
Gordon S. (2003) Alternative activation of macrophages. Nat. Rev. Immunol. 3(1), 23-35.
Nelms K, Keegan AD, Zamorano J, Ryan JJ, and Paul WE. (1999) The IL-4 receptor: signaling mechanisms and biologic functions. Annu. Rev. Immunol. 17, 701-738.

Author: Richard Scheuermann and Mike Gold

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