THE IL-4 RECEPTOR: Signaling Mechanisms and Biologic Functions

Abstract

Interleukin-4 is a multifunctional cytokine that plays a critical role in the regulation of immune responses. 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. In turn, these cause the recruitment of mediators of cell growth, of resistance to apoptosis, and of gene activation and differentiation. Here we describe our current understanding of the organization of the IL-4 receptor, of the signaling pathways that are induced as a result of receptor occupancy, and of the various mechanisms through which receptor function is modulated. We particularly emphasize the modular nature of the receptor and the specialization of different receptor regions for distinct functions, most notably the independent regulation of cell growth and gene activation.

Paradoxical Roles of IL-4 in Tumor Immunity

“…Endogenous IL-4 refers to the IL-4 molecules that are generated without human intervention in a physiological or pathological process. Endogenous IL-4 is usually produced by T cells, basophiles and mast cells and its production is strictly regulated by various interacting signals (20,21). The facts, such as which cells produce, when and how much to produce, are mostly unknown now, but presumably should be carefully orchestrated to achieve homeostasis of immune system.…”

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

“…IL-4 is a critical mediator that promotes di erentiation of T helper precursor (Thp) cells into Th2 cells, while suppressing di erentiation of Thp into Th1 cells (Nelms et al, 1999). It is thus important for IgE production (Corry and Kheradmand, 1999;Nelms et al, 1999).…”

“…It is thus important for IgE production (Corry and Kheradmand, 1999;Nelms et al, 1999). IL-4 also plays a role in activation of endothelial cells (Nelms et al, 1999).…”

“…It is thus important for IgE production (Corry and Kheradmand, 1999;Nelms et al, 1999). IL-4 also plays a role in activation of endothelial cells (Nelms et al, 1999). IL-7 is required for development of T cells in thymus (Baird et al, 1999;Hofmeister et al, 1999), while IL-9 stimulates late T cell growth and mast cell growth (Renauld et al, 1995).…”

Analysis of IL4R haplotypes in predisposition to multiple sclerosis

“…9 The IL4R gene is one such candidate, as it encodes a subunit of the interleukin-4 (IL-4) receptor heterodimer, a molecule critical to T helper cell differentiation and commitment. 10 Both the IL-4 receptor and its ligand IL-4 have been shown to be localized to immune cells at the site of active MS lesions in the brain, suggesting a role for these molecules in disease progression. 11 Changes to IL4R amino-acid residues, particularly the Ile50Val, Ser478Pro and Gln551Arg polymorphisms, are proposed to be functionally important and impact IL-4 receptor signaling (see Shirakawa et al 12 and citations therein).…”