Inflammation Enters The ICE Age

Scientists at Vertex Pharmaceuticals in the USA have identified the three-dimensional structure of interleukin-1 beta converting enzyme (ICE), which is believed to play an early and crucial role in activating the body's inflammatory response. Solving the structure is expected to hasten efforts to design specific, low molecular weight inhibitors of ICE that could be used to treat a variety of inflammatory diseases and neurodegenerative disorders. Details of the structure, which was determined using X-ray crystallography, are published in the UK journal Nature (July 28).

The researchers note that elevated levels of IL-1 beta have been detected in septic shock, rheumatoid arthritis, inflammatory bowel disease, diabetes and other autoimmune diseases, and IL-1 beta is also overexpressed in the brains of patients with Alzheimer's disease. Inhibition of IL-1 beta activity has been shown to ameliorate symptoms in several animal models of human inflammatory disease. Furthermore, a recent clinical trial in AD patients has suggested that treatment with anti-inflammatory agents may be preventative (Neurology 44, 227-232 1994 ).

ICE does not appear to be related to any known protease, and its novel structure opens up a whole new avenue of research in the design of new drugs. "As the understanding of the events of inflammation has unfolded, the significance of ICE as a key switch for the process has become very well recognized," according to David Livingston, project head of Vertex' inflammation program. "A body of promising research establishes the rationale for development of new anti-inflammatory therapies directed at blocking IL-1 activity. For example, inhibiting IL-1 activity, either with an antibody, a receptor antagonist or with soluble IL-1 receptors, has improved symptoms in animal models of inflammatory disorders."