Over the last two decades, we have witnessed an explosion in cytokine biology. Cytokines are potent, low-molecular-weight protein cell regulators produced transiently and locally by numerous cell types. Today, we recognize that cytokines are multifunctional proteins whose biological properties suggest a key role in hematopoiesis, immunity, infectious disease, tumorigenesis, homeostasis, tissue repair, and cellular development and growth.

Cytokines usually act as signaling molecules by binding to their own glycoprotein receptors on cell membranes. This initial interaction is followed by a relay of the signal to the cell nucleus. Signal transduction is mediated as in many hormone-receptor systems via kinase-mediated phosphorylation of cytoplasmic proteins. In fact, tyrosine kinase activity is intrinsic to many cytokine receptors. Because of their role in multiple immunologic activities, cytokines are mentioned throughout this chapter. In following text we describe major cytokines and their functions.

Classification and Functions

Cytokines can be categorized into groups based on their common functions. Examples of functional categories include immunoregulatory, proinflammatory, anti-inflammatory, chemokines, adhesion molecules, and growth and differentiation. Because of its major role in antigen presentation, an important immunoregulatory cytokine is IFN-γ. Proinflammatory cytokines are commonly seen in infectious diseases, and they include IL-1, IL-6, TNF-α, and the IFNs. The anti inflammatory cytokines include TGF-β, IL-10, IL-11, and IFN-β. These may be required to dampen or downregulate an overactive inflammatory response. Cytokines that have a key role in growth and differentiation include the colony stimulating factors (CSFs) and stem cell factor. Selected cytokines, their sources, and their main activities are identified in Table 1.

Tale1. Selected Cytokines: Production and Activities

Cytokines in Immune Cell Development and Host Defense to Infections

 Naïve CD4+ T cells can differentiate into different lineages depending on the exogenous cytokine environment. Th1 cells develop in the presence of IL-12; Th2 cells develop in the presence of IL-4; Th17 cells develop in the presence of TGF-β, IL-6, and IL-23; Tfh cell differentiation begins in the presence of IL-6; and T reg cells are formed in the presence of TGF-β alone. Each of these five T-cell lineages produces cytokines that play a pivotal role in host defense against selective microorganisms. Th1 cells produce IL-2 and IFN-γ, cytokines that can effectively control virus infections and intracellular organisms such as mycobacteria and T. gondii. IFN-γ is a key activator of macrophages and cytotoxic CD8+ T cells. Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13, cytokines that drive IgE responses and help control parasitic infections. Th17 cells produce IL-17, a cytokine that attracts neutrophils and plays protective host defense roles at the epithelial and mucosal barriers. IL-17 has been shown to limit infections in the skin against Staphylococcus aureus, in the colon against Citrobacter rodentium, in the lung against Klebsiella pneumoniae, in the mouth against Candida albicans, and in the vagina against Chlamydia. IL-17 has also been shown to inhibit fungal infections caused by Pneumocystis carinii. Recent studies have shown that mutations in IL-17 and IL-17 receptor genes predispose individuals to chronic mucocandidiasis caused by C. albicans. Tfh cells participate in antibody production. Finally, T regs are regulatory T cells that help suppress T-cell proliferation and maintain tolerance to self-antigens. It has been suggested that T regs functions are facilitated, in part, by the production of immunosuppressive cytokines, IL-10 and TGF-β.

This analysis of T-cell differentiation demonstrates how T-cell subsets secrete their own set of cytokines that have dis tinct regulatory properties. Thus, cytokines orchestrate the type of protective immune response that is generated.

Clinical Applications

Today, there are at least four major clinical applications of cytokines. First, cytokines can serve as biomarkers of disease and provide clues for mechanisms of disease. For example, the proinflammatory cytokines TNF-α, IL-1, and IL-6 can be detected in the sera of patients with septic shock. These cytokines appear to play a critical role in the development of septic shock, and tracking their presence may be of prognostic value in severe sepsis. Second, the measurement of cytokine production in vitro is a useful monitor of immune status. T-cell function can be monitored by the ability of the T cells to produce IFN-γ. This is currently being used to identify tuberculosis (TB) reactivity and is discussed later. Third, recombinant cytokines are key therapeutic agents. An example of this is seen with the IFN molecules. The FDA has approved the use of IFN-α for hepatitis C infections, IFN-β for multiple sclerosis, and IFN-γ for chronic granulomas disease (CGD). Fourth, cytokines can be targets of therapy. Recently, cytokine receptor antagonists and anticytokine monoclonal antibodies both that downregulate pathogenic responses to exaggerated cytokine production have been used as effective treatments. Examples of this approach are the inhibitors of TNF-α used to manage rheumatoid arthritis (RA) and inhibitors of IL-2 and IL-15 used in transplantation and cancer.

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مواضيع ذات صلة

Complement Deficiencies and Pathogen Evasion

Complement Pathways

T Cells

Antibody Responses

Immunoglobulin Genes and Generation of Diversity

Immunoglobulin Classes

Immunofluorescence

Chemiluminescence

Enzyme Immunoassay

Capillary Electrophoresis

Antibody Structure and Function

B Cell Receptor for Antigen