Blockade of IL-1-beta-Converting Enzyme Decreases Intestinal Inflammation
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WESTPORT, CT (Reuters Health) Oct 23 - Inhibition of interleukin-1-beta-converting enzyme (ICE, caspase-1) reduces the inflammation associated with induced colitis in mice, according to a report released today in the Proceedings of the National Academy of Sciences for October 23.
When Dr. Britta Siegmund of the University of Colorado Health Sciences Center in Denver and colleagues fed dextran sulfate sodium (DSS) to wild-type mice and to ICE knockout mice, 30% weight loss occurred in the wild-type mice but not in the knockout mice. Wild-type mice treated with IL-1 receptor antagonist showed 14% weight loss.
"ICE deficiency is associated with a more pronounced effect compared with single blockade of IL-1 or IL-18," the authors write. They propose that the protection of the knockout mice from DSS-induced colitis was due to combined blockade of the two interleukins, although they acknowledge that "ICE could cleave additional — as yet unknown — substrates that participate in intestinal inflammation."
With long-term administration of DSS there was 7% weight loss in wild-type mice over a 30-day period, versus 4% weight gain in knockout mice. In control wild-type mice not fed DSS, there was 7% weight gain over the same length of time.
"The intriguing thing about inhibition of ICE is that there are orally available ICE inhibitors currently in clinical trial for rheumatoid arthritis," Dr. Siegmund told Reuters Health. "Once they are approved, it would be easy to conduct clinical trials in patients with inflammatory bowel disease."
"Right now patients who don't respond to steroids get infliximab...as their last option," she added. "Infliximab has a long half-life, 1 to 2 months. If side effects occur, we can't do anything, because these antibodies persist."
She noted that just 2 weeks ago, researchers reported reactivation of tuberculosis in patients who began using infliximab. "Therefore, there are advantages to a small protein that would inhibit ICE, but would be rapidly cleared from the system."
Proc Natl Acad Sci USA October 23, 2001. |
