Leukocytes and tissue cells
IL-17 is an unusual cytokine because neither it nor its receptor is homologous to any other known cytokine-receptor pair. The IL-17 family includes six structurally related proteins, of which IL-17A and IL-17F are the most similar, and the immunologic activities seem to be mediated primarily by IL-17A. IL-17A and IL-17F are produced mainly by TH17 cells, whereas the other members of the family are produced by diverse cell types. IL-17 receptors are multimeric and expressed on a wide range of cells. Their structure and signaling mechanisms are not well defined.
• IL-17 induces neutrophil-rich inflammatory reactions. It stimulates the production of chemokines and other cytokines (such as TNF) that recruit neutrophils and, to a lesser extent, monocytes to the site of T cell activation. It also enhances neutrophil generation by increasing the production of G-CSF and the expression of its receptors.
• IL-17 stimulates the production of antimicrobial substances, including defensins, from numerous cell types.
IL-22 is a member of the IL-10 cytokine family. It is produced by activated T cells, particularly TH17 cells, and by NK cells. The actions of IL-22 appear contradictory. Some studies indicate that it contributes to inflammation and tissue injury, but the bulk of the available data suggests that it is produced in epithelial tissues, especially of the skin and gastrointestinal tract, and serves to maintain epithelial integrity, mainly by promoting the barrier function of epithelia and by stimulating repair reactions.
IL-21 is produced by activated CD4+ T cells, including Th17 cells, which has a wide variety of effects on B and T cells and NK cells. The IL-21 receptor belongs to the type I cytokine receptor family, consists of a ligand-binding chain and the yc subunit, and activates a JAKSTAT signaling pathway in which STAT3 is especially prominent. An important function of IL-21 is in antibody responses, especially the reactions that occur in germinal centers (see Chapter 11). IL-21 is required for the generation of follicular helper T cells and is also produced by fol-licular helper cells and stimulates B cells in germinal centers. IL-21 has also been shown to promote the differentiation of TH17 cells, especially in humans, providing an autocrine pathway for amplifying TH17 responses. Some of the other reported actions of IL-21 include increasing the proliferation and effector function of CD8+ T cells and NK cells.
The principal effector function of TH17 cells is to induce neutrophilic inflammation, which serves to destroy extracellular bacteria and fungi (see Fig. 10-10). The ability of IL-17 to recruit neutrophils accounts for the central role of TH17 cells in adaptive immune reactions in which neutrophilic inflammation is prominent. The recruited neutrophils ingest and kill extracellular microbes, including fungi and bacteria. The importance of this role of Th17 cells is illustrated by the inherited disease called the hyper-IgE syndrome (or Job's syndrome), which is characterized by increased susceptibility to cutaneous fungal and bacterial infections, and is caused by mutations in the transcription factor STAT3, which is essential for the development of TH17 cells (see Chapter 9).
TH17 cells are also important in the pathogenesis of to many inflammatory diseases, such as psoriasis, inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis. Antibodies that block the development or functions of TH17 cells are in clinical trials for several of these diseases. TH1 and TH17 cells may both be present in the lesions in these diseases, and their relative contribution to the development and propagation of the disorders is an area of active research. TH17 cells may also serve to maintain normal epithelial function in the gut and skin, mainly by virtue of the actions of IL-22.
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