The interleukins represent another large family of cytokines, with at least 33 different constituent members (IL-1 to IL-33) having been characterized thus far. Most of these polypeptide regulatory factors are glycosylated (a notable exception being IL-1) and display a molecular mass ranging from 15 to 30 kDa. A few interleukins display a higher molecular mass, e.g. the heavily glycosylated, 40 kDa, IL-9.
Most of the interleukins are produced by a number of different cell types. At least 17 different cell types are capable of producing IL-1, and IL-8 is produced by at least 10 distinct cell types. On the other hand, IL-2, -9 and -13 are produced only by T-lymphocytes.
Most cells capable of synthesizing one interleukin are capable of synthesizing several, and many prominent producers of interleukins are non-immune system cells (Table 9.1). Regulation of interleukin synthesis is exceedingly complex and only partially understood. In most instances, induction or repression of any one interleukin is prompted by numerous regulators (mostly additional cytokines). IL-1, for example, promotes increased synthesis and release of IL-2 from activated T-lymphocytes. It is highly unlikely that cells capable of synthesizing multiple interleukins concurrently synthesize them all at high levels.
Nearly all of the interleukins are soluble molecules (one form of IL-1 is cell associated). They promote their biological response by binding to specific receptors on the surface of target cells. Most interleukins exhibit paracrine activity (i.e. the target cells are in the immediate vicinity of the producer cells), although some display autocrine activity (e.g. IL-2 can stimulate the growth and differentiation of the cells that produce it). Other interleukins display more systematic endocrine effects (e.g. some activities of IL-1).
The signal transduction mechanisms by which most interleukins prompt their biological response are understood, in outline at least. In many cases, interleukin cell surface receptor binding is associated with intracellular tyrosine phosphorylation events. In other cases, serine and threonine residues of specific intracellular substrates are also phosphorylated. For some interleukins,
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 9.1 Many cell types are capable of producing a whole range of interleukins. T-lymphocytes are capable of producing all the interleukins, with the possible exception of IL-7 and IL-15. Many cell types producing multiple interleukins can also produce additional cytokines. For example, both macrophages and fibroblasts are capable of producing several interleukins, CSFs and PDGF
Vascular endothelial cells
IL-l, IL-6, IL-l0, IL-l2 IL-3, IL-5 IL-l, IL-6, IL-8 IL-l, IL-6, IL-8, IL-ll IL-l, IL-6, IL-8, IL-l0
receptor binding triggers alternative signal transduction events, including promoting an increase in intracellular calcium concentration, or inducing hydrolysis of phosphatidylethanolamine with release of diacyl glycerol.
The sum total of biological responses induced by the interleukins is large, varied and exceedingly complex. These cytokines regulate a variety of physiological and pathological conditions, including:
• normal and malignant cell growth;
• all aspects of the immune response;
• regulation of inflammation.
Several interleukins, particularly those capable of modulating transformed cell growth, as well as those exhibiting immunostimulatory properties, enjoy significant clinical interest. As with other cytokines, the advent of recombinant DNA technology facilitates production of these molecules in quantities sufficient to meet actual/potential medical needs. Thus far, only two interleukin-based products have gained approval for general medical use ('Proleukin', an IL-2 and 'Neumega', an IL-11; see later) and these interleukins, along with IL-1, form the focus of much of this chapter. Literature detailing additional interleukins is cited in the 'Further reading' section, to which the interested reader is referred.
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