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Most cytokines act upon or are produced by leukocytes (white blood cells), which constitute the immune and inflammatory systems (Box 4.1). They thus play a central role in regulating both immune and inflammatory function and related processes, such as haematopoiesis (the production of blood cells from haematopoietic stem cells in the adult bone marrow) and wound healing. Indeed, several immunosuppressive and anti-inflammatory drugs are now known to induce their biological effects by regulating the production of several cytokines.
The term ‘cytokine’ was first introduced in the mid-1970s. It was applied to polypeptide growth factors controlling the differentiation and regulation of cells of the immune system. The interferons (IFNs) and interleukins (ILs) represented the major polypeptide families classified as cytokines at that time. Additional classification terms were also introduced, including; lymphokines [cytokines such as interleukin-2 (IL-2) and interferon-g (IFN-g), produced by lymphocytes] and monokines [cytokines such as tumour necrosis factor-a (TNF-a) produced by monocytes]. However, classification on the basis of producing cell types also proved inappropriate, as most cytokines are produced by a range of cell types, e.g. both lymphocytes and monocytes produce IFN-a.
Initial classification of some cytokines was also undertaken on the basis of the specific biological activity by which the cytokine was first discovered, e.g. TNF exhibited cytotoxic effects on some cancer cell lines, colony stimulating factors (CSFs) promoted the growth in vitro of various leukocytes in clumps or colonies. This, too, proved an unsatisfactory classification mechanism, as it was subsequently shown that most cytokines display a range of biological
Biopharmaceuticals: Biochemistry and Biotechnology, Second Edition by Gary Walsh John Wiley & Sons Ltd: ISBN 0 470 84326 8 (ppc), ISBN 0 470 84327 6 (pbk)
Table 4.1. The major proteins/protein families that constitute the cytokine group of regulatory molecules
The interleukins (IL-1 to IL-15)
The interferons (IFN-a, -b, -g, -t, -w)
Colony stimulating factors (G-CSF, M-CSF, GM-CSF) Tumour necrosis factors (TNF-a, -b)
The neurotrophins (NGF, BDNF, NT-3, NT-4/5) Ciliary neurotrophic factor (CNTF)
Glial cell-derived neurotrophic factor (GDNF) Epidermal growth factor (EGF)
Fibroblast growth factor (FGF)
Leukaemia inhibitory factor (LIF)
Macrophage inflammatory proteins (MIP-1a, -1b, -2) Platelet-derived growth factor (PDGF)
Transforming growth factors (TGF-a, -b) Thrombopoietin (TPO)
Note: G-CSF = granulocyte colony stimulating factor; M-CSF = macrophage colony stimulating factor; GM-CSF = granulocyte-macrophage colony stimulating factor;
NGF = nerve growth factor; BDNF = brain-derived neurotrophic factor; NT = neurotrophin.
activities, e.g. the major biological function of TNF is believed to be as a regulator of both the immune and the inflammatory response. More recently, primary sequence analysis of cytokines coupled to determination of secondary and tertiary structure reveal that most cytokines can be grouped into one of six families (Table 4.2).
As a consequence of the various approaches adopted in naming and classifying cytokines, it is hardly surprising to note that many are known by more than one name, e.g. interleukin-1 (IL-1) is also known as lymphocyte activating factor (LAF), endogenous pyrogen, leukocyte endogenous mediator, catabolin and mononuclear cell factor. This has led to even further confusion in this field.
During the 1980s, rapid developments in the areas of recombinant DNA technology and monoclonal antibody technology contributed to a greater depth of understanding of cytokine biology:
• genetic engineering allowed production of large quantities of most cytokines. These could be used for structural and functional studies of the cytokine itself, and its receptor;
• analysis of cytokine genes established the exact evolutionary relationships between these molecules;
• detection of cytokine mRNA and cytokine receptor mRNA allowed identification of the full range of sources and target cells of individual cytokines;
• hybridoma technology facilitated development of immunoassays capable of detecting and quantifying cytokines;
• inhibition of cytokine activity in vivo by administration of monoclonal antibodies, and more recently by gene knockout studies, continues to elucidate the physiological and pathophysiological effect of various cytokines.
The cytokine family continues to grow and often a decision to include a regulatory protein in this category is not a straightforward one. The following generalizations may be made with regard to most cytokines:
THE CYTOKINES—THE INTERFERON FAMILY 191
Box 4.1. Leukocytes, their range and function