Chemokines (movement, Greek -kinos ) belong to a family of cytokines , and they are small proteins secreted by cells. The name is derived from their function to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.
Cytokines and chemokines are redundant secreted proteins with growth, differentiation, and activation functions that regulate and determine the nature of immune responses and control immune cell trafficking and the cellular arrangement of immune organs. Which cytokines are produced in response to an immune insult determines initially whether an immune response develops and subsequently whether that response is cytotoxic, humoral, cell-mediated, or allergic. A cascade of responses can be seen in response to cytokines, and often several cytokines are required to synergize to express optimal function.
An additional confounding variable in dissecting cytokine function is that each cytokine may have a completely different function, depending on the cellular source, target, and, most important, specific phase of the immune response during which it is presented. Numerous cytokines have both proinflammatory and anti-inflammatory potential; which activity is observed depends on the immune cells present and their state of responsiveness to the cytokine. For this chapter, cytokines are grouped according to those that are mononuclear phagocytic-derived or T-lymphocytic-derived; that mediate cytotoxic (antiviral and anticancer), humoral, cell-mediated, or allergic immunity; and that are immunosuppressive. The biology of chemokines are then reviewed, grouped by family.
Cytokines and chemokines important in the pathophysiology of allergic disorders are summarized in Table I. The IgE isotype switch results from the activities of IL-4 and IL-13 and is inhibited by IFN-γ and TGF-β. IL-2, IL- 5, IL-6, and IL-9 synergize with IL-4 and IL-13 to enhance IgE secretion. IL-4 is responsible for the differentiation of IL-4–producing lymphocytes and recruitment of these TH2-like cells is promoted by CCL2 (MCP-1). IL-12, IL- 18, and IL-23 inhibit the differentiation of IL-4–producing T cells, and recruitment of these TH1-like cells is mediated by CCL5 (RANTES). IL-5 is the most important eosinophilopoietin and with GM-CSF and IL-3 prolongs the survival of mature eosinophils and activates them. These three cytokines, along with TNF and the interferons, are responsible for generating the activated eosinophils that characterize the asthmatic state. Eosinophilia may also result from selective recruitment by the eosinophil chemotaxins CCL3 (MIP-1α), CCL5, and CCL11 (eotaxin). Mast cell differentiation and proliferation results from the activity of SCF and other cytokines, including IL-3, IL-6, IL-9, IL-10, IL-11, and nerve growth factor to promote mast cell production. Stem cell factor is an important mast cell histamine-releasing factor; whereas CCL2, CCL3, CCL5, and CCL7 (MCP-3) are all basophil histamine- releasing factors. Many cytokines contribute to the inflammatory state of allergic inflammatory disorders. IL- 1, TNF, and IFN-γ increase the expression of endothelial cell adhesion molecules such as ICAM-1 and support the egress of mononuclear cells, neutrophils, and eosinophils into the lungs. Induction of VCAM-1 by IL-4 and IL-13 may promote the selective recruitment of eosinophils, basophils, and lymphocytes. Many cytokines and chemokines may then contribute to the activation of these leukocytes once they reach the airways. Cytokines important in promoting fibrosis and airway remodeling are IL-4, IL-6, IL-11, IL-13, IL-17, and TGF-β.
Cytokines are involved in virtually every facet of immunity and inflammation, including innate immunity, antigen presentation, bone marrow differentiation, cellular recruitment and activation, and adhesion molecule expression. Which cytokines are produced in response to an immune insult determines initially whether an immune response develops and subsequently whether that response is cytotoxic, humoral, cell-mediated, or allergic.