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EGF family Epidermal growth factor
Transforming growth factor-a
Haematopoietins Interleukins 2-7, -9, -13
Granulocyte colony stimulating factor
Granulocyte-macrophage colony stimulating factor
Leukaemia inhibitory factor
Ciliary neurotrophic factor
TNF family Tumour necrosis factor-a and -b
THE CYTOKINES—THE INTERFERON FAMILY 193
• They are very potent regulatory molecules, inducing their characteristic effects at nanomolar (nM) to picomolar (pM) concentrations.
• Most cytokines are produced by a variety of cell types, which may be leukocytes or nonleukocytes, e.g. IL-1 is produced by a wide range of cells including leukocytes such as monocytes, macrophages, natural killer cells (NK cells), B and T lymphocytes, and nonleukocytes such as smooth muscle cells, vascular endothelial cells (a single layer of cells lining blood vessels), fibroblasts (cells found in connective tissue that produce ground substance and collagen fibre precursors), astrocytes (non-neural cells found in the central nervous system) and chondrocytes (cells embedded in the matrix of cartilage).
• Many cell types can produce more than one cytokine, e.g. lymphocytes produce a wide range of ILs, CSFs, TNF, IFN-a and IFN-g. Fibroblasts can produce IL-1, IL-6, IL-8, and IL-11, CSFs, INF-b and TNF.
• Many cytokines play a regulatory role in processes other that immunity and inflammation. Neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) regulate growth, development and maintenance of various neural populations in the central and peripheral nervous system. Erythropoietin stimulates the production of red blood cells from erythroid precursors in the bone marrow.
• Most cytokines are pleiotropic, i.e. can effect a variety of cell types. Moreover, the effect a cytokine has on one cell type may be the same or different to its effect on a different cell type, e.g. IL-1 can induce fever, hypotension and an acute phase response. Granulocyte-colony stimulating factor (G-CSF) is a growth factor for neutrophils, but is also involved in stimulating migration of endothelial cells and growth of haematopoietic cells. IFN-g stimulates activation and growth of T and B lymphocytes, macrophages, NK cells, fibroblasts and endothelial cells. It also displays weak anti-proliferative activity with some cell types.
• Most cytokines are inducable, and are secreted by their producer cell, e.g. induction of IL-2 synthesis and release by T-lymphocytes is promoted by binding of IL-1 to its receptor on the surface of T cells. IFN-as are induced by viral intrusion into the body. In general, potent cytokine inducers include infectious agents, tissue injury and toxic stimuli. The body’s main defence against such agents, of course, lies with the immune system and inflammation. Upon binding to target cells, cytokines can often induce the target cell to synthesize and release a variety of additional cytokines.
• In contrast, some cytokines (e.g. some CSFs and erythropoietin) appear to be expressed constitutively. In yet other instances, cytokines such as platelet-derived growth factor and transforming growth factor (TGF)-b are stored in cytoplasmic granules and can be rapidly released in response to appropriate stimuli. Other cytokines (mainly ones with growth factor activity, e.g. TGF-b, fibroblast growth factor and IL-1) are found bound to the extracellular matrix in connective tissue, bone and skin. These are released, bringing about a biological response upon tissue injury.
• Many cytokines exhibit redundancy, i.e. two or more cytokines can induce a similar biological effect. Examples include TNF-a and -b , both of which bind to the same receptor and induce very similar if not identical biological responses. This is also true of the interferon-a family of proteins and interferon-b, all of which bind the same receptor.
Although all cytokines are polypeptide regulatory factors, not all polypeptide regulatory
factors are classified as cytokines. Classical polypeptide hormones such as insulin, follicle
stimulating hormone (FSH) and growth hormone (GH) are not considered members of the
cytokine family. The distinguishing features between these two groups are ill-defined and in many ways artificial. Originally, one obvious distinguishing feature was that hormones were produced by a multicellular, anatomically distinguishable gland (e.g. the pancreas, the pituitary, etc.) and functioned in a true endocrine fashion — affecting cells far distant from the site of their production. Many initially described cytokines are produced by white blood cells (which do not constitute a gland in the traditional sense of the word) and often function in an autocrine/ paracrine manner. However, even such distinguishing characteristics have become blurred. Erythropoietin (EPO), for example, is produced in the kidney and liver and acts in an endocrine manner — promoting production of red blood cells in the bone marrow. EPO could thus also be considered to be a true hormone.