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© Dirk Biddle
Each of the descriptions in previous sections of the blood immune cells and some of their interactions, while fairly straightforward on the surface, belies the incredible complexity of the underlying processes. Each leucocyte is often involved in a multi-functional process where complex bio-molecular chain-reactive events, initiated by the presence of pathogens or toxins and mediated by cytokines, ends up involving many more kinds of leucocyte in varying proportion, each triggering various functionality in the other. In this and coming sections some of that diverse, interactive and (usually) amazingly harmonious functionality is outlined.
Cytokines are a class of immuno-regulatory proteins such as interleukin (IL),
tumour necrosis factor (TNF), and
interferon (IFN), that are secreted by cells, especially of the immune system, and are produced as a result of inflammatory processes within the body. They are mediatory chemicals produced in order to communicate and orchestrate an attack on unwanted infections and altered cells. Table 1 provides their names and outlines the principle sources and principle activities of each of the cytokines.
Table 1. The cytokines: principle sources and principle activities.
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Name
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Source
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Principle Activities
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| IL-1 | Monocytes, macrophages, dendritic cells | TH and B-cell activation; stimulates protein synthesis; increases the expression of adhesion molecules on endothelial cells of the vasculature allowing translocation of immune cells from the blood into the tissue; causes fever; pro-inflammatory |
| IL-2 | T-cells (CD4+) | Stimulates T-cell (CD8+) proliferation independent of antigen; also proliferation and maturation of other T-cells (CD4+); stimulates NK cell activity. |
| IL-3 | Mitogen activated T-cells, epithelial cells, astrocytes | Haematopoietic colony-stimulating factor for bone marrow stem cells and mast cells. |
| IL-4 | T-cells (TH2) | Stimulates B-cell proliferation and differentiation; induces the expression of class II major histocompatibility complex and Fc receptors on B-cells; with IL-10 decreases macrophage activity. |
| IL-5 | T-cells | Terminal B-cell differentiation into IgG antibody secreting (plasma) cells, stimulates eosinophil differentiation and activation in haematopoiesis. |
| IL-6 | T-cells (TH2), monocytes, macrophages, fibroblasts | Stimulates B-cell growth and differentiation into plasma cells; growth factor for hybridomas and plasmacytomas; T-cell proliferation; strongly stimulates hepatocytes to make acute phase proteins in response to inflammation. This cytokine is always found in increased levels in sites of inflammation and is likely very important in a number of undescribed ways in inflammatory regulation; causes fever; pro-inflammatory. |
| IL-7 | Bone marrow stromal cells | Early B-cell precursor growth and (with IL-2) mature T-cell activation |
| IL-8 | Macrophages, T-cells, fibroblasts, endothelial cells, keratinocytes | Powerful neutrophil activation and attraction (chemotactic); T-cell attraction; pro-inflammatory. |
| IL-9 | Mitogen activated T-cells | Stimulates the proliferation of erythrocyte precursor cells; regulator of haematopoiesis; enhances mast cell growth; acts synergistically with erythropoietin. |
| IL-10 | T-cells (TH2), some B-cells | Acts on macrophages to inhibit cytokine production in order to downregulate TH1 type T-cells; downregulates MHC II expression on antigen presenting cells; co-regulates mast cell growth. |
| IL-11 | Bone marrow stromal cells | Stimulates T-cell dependent B-cell maturation; megakaryopoiesis; myeloid differentiation, regulates bone marrow adipogenesis. |
| IL-12 | Macrophages | Initiator of cell-mediated immunity; stimulates TH1 type T-cell proliferation; enhances NK-cells lytic activity; induces interferon production; inhibits IgE antibody synthesis; role in viral immunity. |
| IL-13 | T-cells | B-cell proliferation and differentiation and immunoglobulin (antibody) production; inhibits IL-6 production from monocytes; inhibits IL-1, IL-8, & TNF production. |
| IL-14 | Dendritic cells, T-cells | Induces B-cell proliferation, inhibits immunoglobulin (antibody) secretion, and selectively expands certain B-cell subpopulations (B-memory cells). |
| IL-15 | T-cells | Stimulates the proliferation of T-cells and shares biological activities with IL-2; induces B-cell proliferation and differentiation. |
| IL-16 | T-cells | Stimulates the migration of CD4+ T-cells and monocytes. It has been reported to suppress HIV replication. |
| IFNα | Most leucocytes | Anti-viral |
| IFNβ | Most leucocytes | Anti-viral |
| IFNγ | Fibroblasts, T-cells (TH1), NK-cells | Activates macrophages; increases the expression of class II MHC on APCs; role in many different types of immune responses such as delayed type hypersensitivity; role in antibody production and viral infection; pro-inflammatory. |
| TGFβ | Macrophages, lymphocytes | Increases IL-1 production by activated macrophages; induces a class switch to IgA antibody by proliferating B cells; acts as a chemo-attractant for monocytes and macrophages; stimulates wound healing; growth inhibitor for all lymphocyte cell types; downregulates leucocyte adhesion. |
| TNFα | Macrophages | Tumour killing; pro-inflammatory. |
| TNFβ | T-cells | Tumour killing; enhances phagocytosis; cytolytic; pro-inflammatory. |
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Interleukin: Interleukin-1 inhibitors are the first well-described proteins involved in the feedback regulation of interleukin activities. The origin and functions of the two most novel cytokines, interleukin-11 and interleukin-12 (also referred to as natural killer cell stimulatory factor), have only recently begun to be understood. (OMD)
Tumour Necrosis Factor: (TNF) A protein that is produced chiefly by monocytes and macrophages in response especially to endotoxins. It mediates inflammation and induces the destruction of some tumor cells and the activation of white blood cells (leucocytes). (M+)
TNF was originally described as a tumour inhibiting factor in the blood of animals exposed to bacterial lipopolysaccharide or Bacille Calmette-Guerin, TNF preferentially kills tumour cells in vivo and in vitro. It causes necrosis of certain transplanted tumours in mice and inhibits experimental metastases. Human Tumour Necrosis factor alpha is a protein of 157 amino acids and has a wide range of pro inflammatory actions. Usually considered a cytokine. (OMD)
TNF has two forms, TNF-alpha and TNF-beta.
Interferon: A family of glycoproteins derived from human cells which normally has a role in fighting viral infections by preventing virus multiplication in cells.
They are secreted by vertebrate cells in response to a wide variety of inducers and confer resistance against many different viruses, inhibit proliferation of normal and malignant cells, impede multiplication of intracellular parasites, enhance macrophage and granulocyte phagocytosis, augment natural killer cell activity, and show several other immunomodulatory functions.
Interferon-alpha is made by leucocytes and interferon-gamma by fibroblasts after viral infection. Interferon-alpha and -beta are also called type I interferons and interferon-gamma Type II - more usually classed as cytokines. (OMD)
Hydrogen Peroxide: An unstable compound (H2O2) used especially as an oxidizing and bleaching agent and as an antiseptic. (M+)
Hydrogen peroxide is produced by vertebrate phagocytes and is used in bacterial killing (the myeloperoxidase halide system). (OMD)
Superoxide Anions: A harmful derivative of oxygen capable of oxidative destruction of cell components. (OMD)
Hydroxyl Radicals: Hydroxyl. The univalent radical OH. This radical is characteristic of hydroxides, oxygen acids, alcohols, glycols, phenols, and hemiacetals. (OMD)
Bacteria: One of the two major classes of prokaryotic organism (the other being the Cyanobacteria). Bacteria are small (linear dimensions of around 1 m), non-compartmentalised, with circular DNA and ribosomes of 70S. Protein synthesis differs from that of eukaryotes and many antibacterial antibiotics interfere with protein synthesis, but do not affect the infected host. Recently bacteria have been subdivided into Eubacteria and Archaebacteria, although some would consider the Archaebacteria to be a third kingdom, distinct from both Eubacteria and Eukaryotes. The Eubacteria can be further subdivided on the basis of their staining using Gram stain. Since the difference between gram-positive and gram-negative depends upon a fundamental difference in cell wall structure it is therefore more soundly based than classification on gross morphology alone (into cocci, bacilli, etc.). (OMD) +++ Any of a group (as kingdom Procaryotae or kingdom Monera or the former class Schizomycetes) of prokaryotic unicellular round, spiral, or rod-shaped single-celled microorganisms that are often aggregated into colonies or motile by means of flagella, that live in soil, water, organic matter, or the bodies of plants and animals, and that are autotrophic, saprophytic, or parasitic in nutrition and important because of their biochemical effects and pathogenicity. (M+)
Cytokines:Substance produced by a leucocyte that acts upon another cell. Small proteins or biological factors (in the range of 5-20 kD) that are released by cells and have specific effects on cell-cell interaction, communication and behaviour of other cells. Not really different from hormones, but the term tends to be used as a convenient generic shorthand for interleukins, lymphokines and several related signaling molecules such as TNF (tumour necrosis factor alpha) and interferons. Generally growth factors would not be classified as cytokines, though TGF is an exception. Rather an imprecise term. Chemokines are a subset of cytokines. (OMD)