Stephen T Smiley and Michael J Grusby, Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts, USA

The cytokine interleukin 4 (IL-4) is produced by several subsets of lymphoid cells and has pleiotropic actions on a variety of effector cells of the immune system (Table 1). Its major roles include promoting type 2 T helper (TH2) cell differentiation, immunoglobulin E (IgE) secretion and eosinophil recruitment.

The human and murine IL-4 genes map to human chromosome 5 and mouse chromosome 11 and encode proteins that are comprised of 153 and 140 amino acid residues, respectively. Despite sharing 50% amino acid identity, human IL-4 is inactive on mouse cells and murine IL-4 is inactive on human cells. While natural IL-4 is an 18-20 kDa glycoprotein, recombinant IL-4 lacking glycosylation is fully active. As for most secreted polypeptides, IL-4 contains an N-terminal signal sequence that is post-translationally cleaved.

Table 1 Pleiotropic functions of IL-4

• Acts as a costimulant for growth in B cells, T cells and mast cells.

• Increases the survival of cultured B cells, T cells and other hematopoietic cell types

• Induces the expression of MHC class II on B cells and monocytes and CD23 on B cells

• Directs immunoglobulin class switching to the lgG1 and IgE isotypes

• Directs T helper cell differentiation to the TH2 type

• Diminishes the inflammatory functions of monocytes and macrophages while enhancing their antigen presenting functions

• Can inhibit the growth of transplanted tumors in vivo and can diminish the growth of certain cancer cells in vitro

• Induces growth and chemotaxis in human fibroblasts and the production of IL-6, extracellular matrix proteins and ICAM-1

• Regulates expression of VCAM-1 on human endothelial cells and VLA-4 on T cells and eosinophils

• Reduces CI secretion by intestinal epithelial cells

IL-4 is produced by several subsets of activated lymphoid cells. TH2 cells are particularly important sources of this cytokine, as they are critical for initiating humoral immunity against extracellular pathogens. In addition to secreting IL-4, Tn2 cells also require IL-4 for their own development. It has been suggested that specialized T cells that expresses natural killer (NK) cell markers and secrete large amounts of IL-4 immediately after T cell receptor stimulation produce the IL-4 that promotes TH2 cell differentiation. However, TH2 cell differentiation can proceed normally in strains of genetically altered mice that lack these NK-like T cells. Activated mast cells, basophils and y/8 T cells can also produce IL-4 and thus may be other sources of the IL-4 that is required for Th2 cell differentiation.

Secretion of IL-4 is transcriptionally regulated and, as such, the IL-4 promoter has been extensively studied. Functionally important binding sites for AP-1 and NF-AT transcription factors are present in the IL-4 promoter. However, AP-1 and NF-AT also bind to the promoters of other cytokine genes expressed independently of IL-4, suggesting that cell-specific expression of IL-4 is dictated by additional factors. Indeed, recent studies indicate that activity of the proto-oncogene c-maf may be responsible for the specific transcription of the IL-4 gene in Tn2 cells.

As is the case with other cytokines, IL-4 elicits biological responses by interacting with a specific cell surface receptor. The IL-4 receptor is expressed on a wide variety of cell types including T and B lymphocytes, macrophages, fibroblasts, keratinocvtes and endothelial cells. The receptor is composed of at least two chains: a 140 kDa ligand-specific a chain and a 75 kDa yc chain. The a chain is also a component of the IL-13 receptor, while the yc chain is shared by several other cytokine receptors, including those for IL-2, IL-7, IL-9 and IL-15.

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