Cytokines
Last updated: November 8, 2014
Synonyms: Other names, such as interleukin (IL), reflect the importance of cytokines in intercellular interactions between white blood cells. Other names reflect the predominant cell type from which they derive (e.g., monokines, lymphokines) or the functions with which they were first associated (e.g., B-cell growth factor, endogenous pyrogen, or chemokine).
Definition: To perform their functions optimally, cells of the immune system must communicate with each other. Such communication can be accomplished in two ways. Cells may physically touch each other, relaying information via specific cell-surface receptors (e.g., adhesion molecules). Alternatively, cells may secrete molecules (cytokines) that interact with receptors on other cells. Many cytokines are small glycoproteins with varying cellular origins (Table 9) that bind with high affinity to specific receptors.
Role: Cytokines serve critical roles in (a) immune reactions (they modulate antigen presentation, activation of immunocompetent cells, and the determination of whether immune reactions are predominantly humoral or cellular); (b) inflammatory reactions (cytokines cause recruitment and activation of cells and also initiate the acute-phase response); and (c) hematopoiesis (several cytokines promote the growth and maturation of various cell lineages).
More than 50 cytokines and their receptors have been identified, and the range of functions of these molecules expands continuously. Cytokines may exert their varied effects in an autocrine (acting on the cell from which they were secreted), paracrine (acting on cells in the same area), or endocrine (acting on distal cells) manner. Cytokines are typically pleiotropic, i.e., a single cytokine typically has numerous functions and acts on various cell types. In addition, there is significant redundancy; several cytokines may have overlapping functions. Rather than acting in isolation, cytokines act in an organized network. Some cytokines have antagonistic functions; others are synergistic.
| Table: Major Cytokines, Cellular Sources, and Biologic Functions | ||||
| Cytokines | Major Sources | Functions | ||
|---|---|---|---|---|
| IL-1 | Macrophages, many other cell lines | Activates lymphocytes, stimulates acute-phase response, CNS effects (fever, increased sleep, anorexia), bone and cartilage destruction, stimulates various inflammatory mediators (leukotrienes, prostaglandins), increases IL-6, activates endothelium | ||
| IL-2 | T cells, NK cells | Critical autocrine growth factor for T cells; increases killing of tumors by NK cells (creating LAK cells) | ||
| IL-3 | T cells | Stimulates growth of multiple cell lineages | ||
| IL-4 | T cells, mast cells | Increases antibody synthesis (e.g., IgE), may inhibit cell-mediated T-cell responses | ||
| IL-5 | T cells, mast cells | Promotes maturation, activation, and survival of eosinophils | ||
| IL-6 | Macrophages, lymphocytes | Promotes terminal B-cell maturation, synthesis of acute-phase reactants | ||
| IL-8 | Macrgphages | A “chemokine,” promotes endothelial cells chemotaxis of neutrophils to inflammatory sites | ||
| IL-10 | Macrophages, T cells | Inhibits synthesis of other cytokines (e.g., IL-2, IFN–y) | ||
| IL-12 | Macrophages, dendritic cells | Differentiation/maturation of Th1 cell, T cell cytotoxicity, B cell activation | ||
| IL-17 | Th17 cells, fibroblasts | Chemokine release, fibroblast cytokine release, ↑MMP release, osteoclastogenesis, hematopoiesis, ↓chondrocyte GAG synthesis Leukocyte cytokine production |
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| IL-18 | Th1 cells, NK cells, B cells | Proinflammatory; induction of IFNγ | ||
| IL-21 | NK, CD4+, Th17 T cells | Differentiation of lymphoid and myeloid cells, T cell proliferation, differentiation of B cells, enhanced NK cytotoxicity; has antiviral/antitumor effects | ||
| IL-22 | Th17 cells, CD8+cells, NK cells, γδ T cells | Acute phase response, Keratinocyte activation | ||
| IL-23 | Macrophages, dendritic cells, keratinocytes | Stimulates Th17 cells to produce IL-17A and IL-22 | ||
| IL-33 | Epithelial cells; monocytes; smooth muscle cells; keratinocytes | Promote Th2 cell activation, mast cell activation, and cytokine production | ||
| TNF | Macrophages, lymphocytes | Stimulates acute-phase response, endothelial cells CNS effects (fever, increased sleep, cachexia), bone and cartilage destruction, increases IL-1, IL-6, IL-8, activates endothelium | ||
| IFN-α/β (Type I interferons) | Many cell types | viral replication MHC I expression | ||
| IFN-y | T cells | Critical cytokine for macrophage activation, activates endothelium, inhibits humoral response | ||
| GM-CSF | T cells | Stimulates growth of macrophage, endothelial cells granulocyte precursors | ||
| RANK ligand | Stromal cells; osteoblasts; T cells | Stimulates bone resorption via osteoclast maturation and activation. Modulation of T cell-DC interaction. | ||
| IL, Interleukin; CNS, central nervous system; NK, natural killer; LAK, lymphocyte-activated killer cell; TNF, tu- mor necrosis factor; IFN, interferon; GM-CSF, granulocyte-macrophage colony-stimulating factor. | ||||
Disease Associations: The role of cytokines in various diseases has been illustrated by demonstrating increased concentrations of some cytokines in specific conditions. For example, the synovial fluid of patients with inflammatory arthritides such as RA contains elevated amounts of the proinflammatory cytokines IL-1 and tumor necrosis factor-a. In addition, the efficacy of various immunosuppressive therapies depends in large part on their ability to inhibit cytokines (e.g., corticosteroids inhibit IL-1, IL-6, and other cytokines; cyclosporine inhibits IL-2). Moreover, specific therapies directed against cytokines, such as anti-cytokine monoclonal antibodies or receptors, are currently being used for various inflammatory diseases.
Method: Several of the listed cytokines are available from special clinical laboratories. Most assays for secreted circulating cytokines are enzyme immunoassays performed on serum or plasma.
Indications: Cytokine levels are not clinically indicated in the diagnosis or monitoring of patients with rheumatic or autoimmune disease. They are primarily used in some research situations to evaluate a patient’s immunologic status or response to biologically specific therapies.
Cost: These tests are expensive. IL-1, $320; IL-6, $230; IL-8, $520; IL-2, $220; IL-2R, $30–205; interferon gamma, $185.
BIBLIOGRAPHY
Charles A. Dinarello. Historical Review of Cytokines. Eur J Immunol. Nov 2007; 37(Suppl 1): S34–S45. PMID; 17972343
