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FIGURE 10-8 Classical and alternative macrophage activation. Subsets of activated macrophages. Different stimuli activate monocytes-macrophages to develop into functionally distinct populations. Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-y, and are microbicidal and involved in potentially harmful inflammation. Alternatively activated macrophages are induced by IL-4 and IL-13 produced by TH2 cells and other leukocytes and are important in tissue repair and fibrosis.

Interleukin-4

IL-4 is the major stimulus for the production of IgE antibodies and for the development of TH2 cells from naive CD4+ helper T cells. IL-4 is the signature cytokine of the Th2 subset and functions as both an inducer and an effector cytokine of these cells.

IL-4 is a member of the four-a-helical cytokine family. The principal cellular sources of IL-4 are CD4+ T lymphocytes of the Th2 subset and activated mast cells. The IL-4 receptor of lymphoid cells consists of a cytokine-binding a chain that is a member of the type I cytokine receptor family, associated with the yc chain shared by other cytokine receptors. This IL-4Rayc receptor signals by the JAKSTAT pathway (JAK3 or JAK4 and STAT6) and by a pathway that involves the insulin response substrate (IRS) called IRS-2. IL-4 and IL-13 activate the STAT6 protein, which induces transcription of genes that account for many of the actions of these cytokines. IL-4 also binds to the IL-13 receptor (described below).

IL-4 has important actions on several cell types.

• IL-4 stimulates B cell Ig heavy chain class switching to the IgE isotype. The mechanisms of class switching are described in Chapter 11. Knockout mice lacking IL-4 have less than 10% of normal IgE levels. IgE antibodies play a role in eosinophil-mediated defense against helminthic (and some arthropod) infections. IgE is also the principal mediator of immediate hypersensitivity (allergic) reactions, and production of IL-4 is important for the development of allergies (see Chapter 19). IL-4 also enhances switching to IgG4 (in humans, or the homologous IgG1 in mice) and inhibits switching to the IgG2a and IgG3 isotypes in mice, both of which are stimulated by IFN-y. This is one of several reciprocal antagonistic actions of IL-4 and IFN-y. IL-13 can also contribute to switching to the IgE isotype.

• IL-4 stimulates the development of TH2 cells and functions as an autocrine growth factor for differentiated Th2 cells. This function of IL-4 was described in Chapter 9.

• IL-4, together with IL-13, contributes to an alternative form of macrophage activation that is distinct from the macrophage response to IFN-y and is described later. In fact, IL-4 and IL-13 suppress IFN-y-mediated classical macrophage activation and thus inhibit defense against intracellular microbes.

• IL-4 (and IL-13) stimulate peristalsis in the gastrointestinal tract, and IL-13 increases mucus secretion from airway and gut epithelial cells. Both these actions contribute to elimination of microbes at epithelial surfaces.

• IL-4 and IL-13 stimulate the recruitment of leukocytes, notably eosinophils, by promoting expression of

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