Cytokines

Cytokines are a diverse group of regulatory proteins or glycoproteins whose classification remains somewhat diffuse (Table 8.1). These molecules are normally produced in minute quantities by the body. They act as chemical communicators between various cells, inducing their effect by binding to specific cell surface receptors, thereby triggering various intracellular signal transduction events. Over the next several chapters we consider various cytokines of therapeutic interest, focusing in particular upon those approved for clinical application.

Most cytokines act upon, or are produced by, leukocytes (white blood cells), which constitute the immune and inflammatory systems (Box 8.1). They thus play a central role in regulating both immune and inflammatory function and in related processes such as haematopoiesis (the production of blood cells from haematopoietic stem cells in the adult bone marrow), as well as in wound healing. Indeed, several immunosuppressive and anti-inflammatory drugs are now known to induce their biological effects by regulating 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 and interleukins represented the major polypeptide families classified as cytokines at that time. Additional classification terms were also introduced, including lymphokines (cytokines such as IL-2 and IFN-y, produced by lymphocytes) and monokines (cytokines such as 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; 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 activities (e.g. the major biological function of TNF is believed to be as a regulator of both the immune and 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 8.2).

Pharmaceutical biotechnology: concepts and applications Gary Walsh © 2007 John Wiley & Sons, Ltd ISBN 978 0 470 01244 4 (HB) 978 0 470 01245 1 (PB)

Table 8.1 The major proteins/protein families that constitute the cytokine group of regulatory molecules3

The interleukins (IL-1 to IL-33) The interferons (IFN-a, -ß, -y, -t, -m) CSFs (G-CSF, M-CSF, GM-CSF) TNFs (TNF-a, -ß)

The neurotrophins (NGF, brain-derived neurotrophic factor (BDNF), NT-3, NT-4/5)

Ciliary neurotrophic factor (CNTF)

Glial cell-derived neurotrophic factor (GDNF)

Fibroblast growth factor (FGF)

Leukaemia inhibitory factor (LIF)

Macrophage inflammatory proteins (MIP-1a, -1ß, -2)

PDGF

Transforming growth factors (TGF-a, -ß) TPO

aM-CSF: macrophage-colony-stimulating factor; NT: neurotrophin.

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