The subject of interleukins is fascinating, but highly complex. These compounds are a type of cytokine; i.e. they are proteins – released by cells that have been activated by antigen – which mediate an immune response by interacting with a specific cell-surface receptor. According to some authorities, interleukins may be regarded as the hormones responsible for regulating our immune and inflammatory responses. Thus they have a huge range of effects throughout the body and this tour covers only a fraction of their activity.

We'll start off with a snapshot of the major sources and effects of different examples. Slightly more detail, including a definition, can be found at here. Both sites confirm that these compounds are involved in many physiological processes, from promoting haematopoiesis to the production of antibodies, so it might be useful to have a quick look at the way that the immune system functions. This explanation from the University of Arizona is very basic, but covers the activation and role of both T-cells and B-cells in the immune response. (Incidentally, the abbreviation MHC used on this page stands for Major Histocompatibility Complex.)

Cell activation is not an all-or-nothing phenomenon but a continuous spectrum of alterations, normally associated with the rapid expression of a number of new genes. The action of interleukins involves the binding of a ligand to its corresponding membrane receptor. This induces changes which transmit a signal via a cascade of reactions and eventually modulate gene activity in the nucleus. Most interleukins utilise the Jak-STAT pathway. If you are feeling brave(!) you can learn a great deal about this pathway, with particular reference to haematopoiesis, at bloodjournal.org,but it could not be described as an easy read.

If you stayed with the Cytokines Online Pathfinder Encyclopaedia, this is an excellent source of information on many different aspects of interleukins. For example, the main page on IL-1 starts by outlining the sources and protein characteristics of IL-1-alpha and IL-1-beta before moving on to their gene structure and Type-1 and Type-2 receptors. There are also extensive sections on biological activity, assay methods and clinical use – and according to the index this is only one of more than 60 pages on IL-1!

A particularly interesting concept is that interleukins provide the link between body and mind, so are responsible for emotions affecting health, and for disease affecting emotional wellbeing. In an address given two years ago, Dr Esther Sternberg of the US National Institutes of Health pointed out that interleukins communicate with the brain via many routes and can stimulate its hormonal stress response, resulting in feelings and emotions that may be described as 'sickness behaviour'. Furthermore, as interactions between the immune and nervous systems are important in many different diseases, a better understanding of the mechanisms involved promises innovative new treatments.

One feature of interleukins, and cytokines in general, is that they tend to act locally i.e. they exhibit paracrine rather than endocrine activity. High concentrations are maintained close to the site of secretion by binding to glycosaminoglycans (GAGs) and this is pivotal in the activation and regulation of immune responses. Of the four classes of GAG, heparin/heparan sulphate compounds have the most variable structure and appear to have the greatest diversity of function. Research into the binding of IL-2, IL-6 and IL-12 to heparin aims to evaluate its biological importance and determine any possible clinical applications.

The role of interleukins in various pathological processes has been studied. In asthma, for example, interleukins 4, 9 and 13 may be responsible for a first-phase attack by stimulating the production and release of immunoglobulin E (IgE), which in turn leads to the release of leukotrienes. Moreover, IL-5 appears to contribute to a late-phase inflammatory response by attracting eosinophils that accumulate and remain in the airways. The progression of atherosclerosis is thought to involve pro-inflammatory cytokines such as IL-6 and pre-eclampsia is associated with increased plasma concentrations of IL-10, which may be a protective response to maternal immunorejection.

However, much research into interleukins has investigated their role in malignancy, since tumour growth disrupts their activation and regulation, and consequently their receptors. At anticancer.net there is a list of the roles played by most interleukins in neoplastic development. For example, IL-1-alpha slows down tumour growth and lowers metastatic potential, while IL-1-beta increases the regeneration of tissue and stimulates the metastatic process. Also, IL-2 induces the activation of practically all cytotoxic cells and increases the cytotoxic functions of T-killer cells and NK-cells, while IL-11 is expressed by approximately 20% of invasive primary breast tumours and is associated with a statistically significant higher rate of bone metastases - click here for details. Earlier this year the discovery was announced of IL-24 and two receptors in colon cancer – the first interleukin to be found along with its receptors in tumour cells. It was also demonstrated that Il-24 can promote cell growth and prevent cell death.

In the USA and Europe, IL-2 has been approved for the treatment of patients with metastatic renal carcinoma and melanoma. Response rates have been modest, but are felt to represent significant benefit. IL-2 therapy has also elicited responses in other cancers, including those of the ovary, lung, head and neck, breast, bladder and brain, as well as in haematologic malignancies.

A number of studies have been conducted on the use of IL-2 in people with HIV – click here for details. This therapy significantly increases CD4+ cell counts in these patients, possibly by extending the lifespan of these cells, and may enhance immune responses.

However, high dose IL-2 regimens are associated with significant cardiovascular toxicities identical to those of septic shock, including hypotension, a vascular leak syndrome and respiratory insufficiency. Furthermore, in patients receiving IL-2 therapy for cancer, it has also been found to induce depressive symptoms early in the course of treatment.

To sum up, much has been learned about interleukins after a more than a decade of investigation, but despite wide clinical experience and optimistic predictions from preclinical studies, their therapeutic efficacy remains limited. In the future, better characterisation of groups of patients should lead to improved benefits for individuals and more efficient clinical trials.

This tour was submitted by Derrick Garwood, a Freelance Medical Writer and Editor whose can be contacted by email at derrick@ecrivain.globalnet.co.uk.

The details presented here were accurate at the time of publication, but remember that information on the Web has a tendency to change without notice!

To make any comments on this article, or to ask a question of the author, please contact the publisher. If you would like to submit an article please subscribe to our PL Intelligence service.

The opinions expressed in the articles published in this section do not necessarily reflect those of Pharmalicensing or UTEK Corporation. No actions including proposals to or agreements with other companies should be taken by any reader without obtaining specific business or legal advice. Neither the publisher nor the authors accept any liability for any actions or activities undertaken by any reader or other third party as a consequence of these articles or for any errors or omissions therein.