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The exact IL-1-mediated mechanism(s) of signal transduction remain to be clarified. A number of different signal transduction pathways have been implicated, including involvement of G proteins. IL-1 has also been implicated in activation of protein kinase C by inducing the hydrolysis of phosphotidylethanolamine.
The biological activities of IL-1
IL-1 mediates a wide variety of biological activities:
• it is a pro-inflammatory cytokine, promoting the synthesis of various substances, such as eicosanoids, as well as proteases and other enzymes involved in generating inflammatory mediators. This appears to be its major biological function;
• it plays a role in activating B lymphocytes, along with additional cytokines and may also play a role in activating T lymphocytes;
• along with IL-6, it induces synthesis of acute phase proteins in hepatocytes;
• it acts as a co-stimulator of haematopoietic cell growth/differentiation.
The relative prominence of these various biological activities depends largely upon the quantities of IL-1 produced in any given situation. At low concentrations, its effects are largely paracrine, e.g. induction of local inflammation. At elevated concentrations, it acts more in an endocrine manner, inducing systematic effects such as the hepatic synthesis of acute phase proteins, but also induction of fever (hence the name, ‘endogenous pyrogen’) and cachexia (general body wasting, such as that associated with some cancers). Many of these biological activities are also promoted by TNF — another example of cytokine redundancy.
In addition to IL-1 a and -1b, a third IL-1-like protein has been identified, termed IL-1 receptor antagonist (IL-1Ra). As its name suggests, this molecule appears to be capable of binding to the IL-1 receptors without triggering an intracellular response.
IL-1 continues to be a focus of clinical investigation. This stems from its observed:
• immunostimulatory effects;
• ability to protect/restore the haematopoietic process during, or subsequent to, chemotherapy or radiation therapy;
• anti-proliferative effects against various human tumour cell lines grown in vitro, or in animal models.
Most of these effects are most likely mediated not only directly by IL-1 but also by various additional cytokines (including IL-2), induced by IL-1 administration.
The observed effects prompted initiation of clinical trials assessing IL-1’s efficacy in treating:
• bone marrow suppression induced by chemo/radiotherapy;
• various cancers.
The initial findings of some such trials (involving both IL-1 a and IL-1b) proved disappointing. No significant anti-tumour response was observed in many cases, although side effects were commonly observed. Virtually all patients suffered from fevers, chills and other flu-like symptoms. More serious side effects, including capillary leakage syndrome and hypotension, were also observed and were dose-limiting.
IL-1 thus displays toxic effects comparable to administration of TNF (see later) or high levels of IL-2. However, several clinical studies are still under way and this cytokine may yet prove therapeutically useful, either on its own or, more likely, when administered at lower doses with additional therapeutic agents.
Because of its role in mediating acute/chronic inflammation, (downward) modulation of IL-1 levels may prove effective in ameliorating the clinical severity of these conditions. Again, several approaches may prove useful in this regard, including:
• administration of anti-IL-1 antibodies;
• administration of soluble forms of the IL-1 receptor;
• administration of the native IL-1 receptor antagonist.
Kineret is the trade name given to a recently approved product based on the latter strategy. Indicated in the treatment of rheumatoid arthritis, the product consists of a recombinant form of the human IL-1 receptor antagonist. The 17.3 kDa, 153 amino acid product is produced in engineered E. coli and differs from the native human molecule in that it is non-glycosylated and contains an additional N-terminal methionine residue (a consequence of its prokaryotic
CYTOKINES: INTERLEUKINS AND TUMOUR NECROSIS FACTOR 235
expression system). The purified product is presented as a solution and contains sodium citrate, EDTA, sodium chloride and polysorbate 80 as excipients. A daily (s.c.) injection of 100 mg is recommended for patients with rheumatoid arthritis. This inflammatory condition is (not surprisingly) characterized by the presence of high levels of IL-1 in the synovial fluid of affected joints. In addition to its pro-inflammatory properties, IL-1 also mediates additional negative influences on joint/bone, including promoting cartilage degradation and stimulation of bone resorption.
An additional approach to IL-1 downregulation could entail development of inhibitors of the proteolytic enzymes that release the active IL from its inactive precursor. Moreover, such inhibitors could probably be taken orally and, thus, would be suitable to treat chronic inflammation (the alternatives outlined above would be administered parenterally).