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A variety of medical conditions are now believed to be caused or exacerbated by overproduction of certain cytokines in the body. A variety of pro-inflammatory cytokines, including IL-6 and IL-8 as well as TNF, have been implicated in the pathogenesis of both septic shock and rheumatoid arthritis. Inhibiting the biological activity of such cytokines may provide effective therapies for such conditions. This may be achieved by administration of monoclonal antibodies raised against the target cytokine, or administration of soluble forms of its receptor which will compete with cell surface receptors for cytokine binding.
Some cytokines have already gained approval for medical use. Many more are currently undergoing clinical or pre-clinical trials. Over the next few chapters, the biology and potential medical applications of these cytokines will be discussed in detail. The remainder of this chapter concerns itself with the prototypic cytokine family — the interferons.
Interferons (IFNs) were the first family of cytokines to be discovered. In 1957 researchers observed that if susceptible animal cells were exposed to a colonizing virus, these cells immediately become resistant to attack by other viruses. This resistance was induced by a substance secreted by virally-infected cells, which was named ‘interferon’ (IFN). Subsequently it has been shown that most species actually produce a whole range of interferons. Humans produce at least three distinct classes, IFN-a, IFN-b and IFN-g (Table 4.4). These interferons are produced by a variety of different cell types, and exhibit a wide range of biological effects, including:
• induction of cellular resistance to viral attack;
• regulation of most aspects of immune function;
• regulation of growth and differentiation of many cell types;
• sustenance of early phases of pregnancy in some animal species.
No one IFN will display all of these biological activities. Effects are initiated by the binding of the IFN to its specific cell surface receptor present in the plasma membrane of sensitive cells.
Table 4.4. Human interferons (IFNs) and the cells that produce them
Interferon No of distinct
family Additional name IFNs in family Producing cells
IFN-a Leukocyte IFN, B cell IFN, >15 Lymphocytes, monocytes, macrophages
IFN-b Fibroblast IFN, IFN-b-1* 1 Fibroblasts, some epithelial cells
IFN-g Immune IFN, T cell IFN 1 T-lymphocytes, NK cells
*Originally a second cytokine was called IFN-b-2, but this was subsequently found to be actually IL-6.
THE CYTOKINES—THE INTERFERON FAMILY 197
IFN-a and -b display significant amino acid sequence homology (30%), bind to the same receptor, induce similar biological activities and are acid-stable. For these reasons, IFN-a and IFN-b are sometimes collectively referred to as ‘type I interferons’, or ‘acid-stable interferons’. IFN-g is evolutionarily distinct from the other interferons; it binds to a separate receptor and induces a different range of biological activities, and it is thus often referred to as type II interferon.
Due to their biological activities, most interferons are of actual or likely use in the treatment of many medical conditions, including:
• augmentation of the immune response against infectious agents (viral, bacterial, protozoan, etc.);
• treatment of some autoimmune conditions;
• treatment of certain cancer types.
Interferons may be detected and quantified using various bioassays or by immunoassay systems. While such assays were available, subsequent purification, characterization and medical utilization of IFNs initially proved difficult due to the tiny quantities in which these regulatory proteins are produced naturally by the body. By the early 1970s, advances in animal cell culture technology, along with the identification of cells producing increased concentrations of IFNs, made some (mostly IFN-as) available in reasonable quantities. It was not until the advent of genetic engineering, however, that all IFNs could be produced in quantities sufficient to satisfy demand for both pure and applied purposes.
The biochemistry of interferon-a
For many years after its initial discovery, it was assumed that IFN-a represented a single gene product. It is now known that virtually all species produced multiple, closely related IFN-as. Purification studies from the 1970s using high-resolution chromatographic techniques (mainly ion-exchange and gel-filtration chromatography, immunoaffinity chromatography and isoelectric focusing) first elucidated this fact.
In humans at least 24 related genes or pseudo-genes exist, which code for the production of at least 16 distinct mature IFN-as. These can be assigned to one of two families, types I and II. Humans are capable of synthesizing at least 15 type I IFN-as and a single type II IFN-a.