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The IL-4 receptor consists of at least two polypeptides. An 800 amino acid a-chain, which is heavily glycosylated (also known as p140), is primarily responsible for binding IL-4. The second chain is g(c) which, as discussed earlier, is also a constituent of the IL-2 receptor. The molecular details underlining signal transduction remain to be characterized in detail, although both
CYTOKINES: INTERLEUKINS AND TUMOUR NECROSIS FACTOR 237
Figure 5.6. 3-D structure of human IL-4. Photo from Powers et al. (1992), by courtesy of the Protein Data Bank: http://www.pdb.org/
protein tyrosine kinase and breakdown of PIP2 (phosphatidylinositol bisphosphate)-mediated mechanisms have been implicated.
IL-4 has various effects on a number of cell types. Its main target cells appear to be B and T lymphocytes and also monocytes, fibroblasts and endothelial cells. Specific biological effects include:
• promotes proliferation of B cells, as well as growth and differentiation of many T cells including TH2 helper cells, which, in turn, stimulate humoral immunity and cytotoxic T cells. It also stimulates NK cell activity;
• promotes antibody class switching in B cells, resulting in the production of IgE;
• promotes growth of mast cells (along with IL-3);
• inhibits macrophage activation;
• promotes some cell types (especially endothelial cells) to express surface cellular adhesion
molecules. These serve as docking sites for monocytes and eosinophils in particular, and thus these cells are attracted to the vicinity of IL-4 production.
Due to its immunostimulatory effects, IL-4 is being assessed clinically for the treatment of
various cancer types. Its therapeutic potential in this regard remains unclear until further clinical data is generated. Administration of IL-4 does prompt many characteristic cytokine side effects, the severity of which sometimes equates to IL-1 administration.
In some instances, therapeutic benefit might accrue from inhibition of IL-4 activity. This cytokine plays a central role in the induction of immediate hypersensitivity (i.e. allergic) reactions, through processes such as:
• induction of IgE synthesis—which is a major mediator of many allergic reactions;
• its ability to promote congregation of monocytes and eosinophils, which, again, contain cellular mediators of inflammation;
• its growth-promoting effect on mast cells (which harbour granules filled with inflammatory/ allergic substances, such as histamine).
Blocking of IL-4 activity by strategies previously discussed in the context of other cytokines (e.g. administration of soluble receptor fragments, monoclonal antibodies, etc.) thus may have a potential role to play in treating allergies, especially acute life-threatening episodes associated with asthma or anaphylaxis.
IL-6 is a pleiotropic cytokine, synthesized by a variety of cell types (both leukocyte and nonleukocyte), which induces biological effects in a number of cell types — both leukocyte and nonleukocyte (Table 5.6).
The gene coding for IL-6 consists of five exons separated by four introns, and is present on chromosome 7. IL-6 is initially synthesized as a 26 kDa, 212 amino acid precursor protein. Subsequent removal of a 28 amino acid signal peptide yields the mature 184 amino acid cytokine, whose molecular mass remains at approximately 26 kDa due to glycosylation (removal of the carbohydrate component appears to have no effect on the biological activity of the molecule). Interestingly, IL-6, produced by fibroblasts and monocyte/macrophages at least, is also phosphorylated at several residues.
The IL-6 receptor, present on IL-6-sensitive cells (Table 5.6), consists of two associated transmembrane polypeptides, a and b. The extracellular domains of both are glycosylated. The 449 amino acid, 80 kDa a-chain (IL-6 Ra) binds IL-6 directly, while the 130 kDa b-chain (IL-6 Rb, gp 130) then initiates intracellular signalling (Figure 5.7).
The exact details of signal transduction remain to be clarified. Binding of IL-6 to the a-chain, however, appears to facilitate direct interaction of the b-chain with a second b-chain. This
Table 5.6. Cells synthesizing and targeted by IL-6. Macrophages, endothelial cells and fibroblasts are probably the major producer cells
Producer cells IL-6 sensitive cells
(i.e. express IL-6 receptor)
T lymphocytes T lymphocytes
B lymphocytes Activated B lymphocytes
Bone marrow stromal cells Epithelial cells
Endothelial cells Hepatocytes
Keratinocytes Neural cells