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A paradox helps explain how aspirin works

Even though aspirin's pain-killing capacity was well known to Hippocrates in the fifth century B.C., exactly what it does remains somewhat of a mystery. Now, Johns Hopkins researchers have shown that aspirin inhibits interleukin-4, a protein involved in allergic reactions and inflammation.

"The finding appears to explain some of aspirin's less obvious beneficial effects, such as how the drug might help prevent heart disease or the ravages of rheumatoid arthritis," says Vincenzo Casolaro, M.D., Ph.D., assistant professor of clinical immunology at Hopkins, reporting in the March issue of Blood.

Aspirin, the world's most used non-steroidal anti-inflammatory drug, provides the mainstay of therapy for inflammatory musculoskeletal disorders and has been shown to be effective in the management and prevention of a wide variety of non-inflammatory conditions, including coronary and cerebral ischemia and possibly gastrointestinal cancer.

Since the 1970s, researchers have known that aspirin works, in part, by inhibiting prostaglandin, a hormone-like substance present in a variety of tissues and body fluids that has many roles, including causing contraction of smooth muscle and promoting inflammation. Specifically, aspirin inhibits an enzyme, cyclo-oxygenase (COX), that catalyzes the generation of prostaglandin from cell membrane fatty acid precursors. But the suppression of prostaglandin production could not fully account for aspirin's effectiveness because, after 15 minutes, aspirin is broken down in the body and becomes salicylic acid, a completely ineffective inhibitor of COX.

By 1994, aspirin was found to actually repress the activation of NF-ΚB, a molecular activator of cytokines, chemicals that trigger inflammation. Casolaro, an allergy researcher, wondered whether IL-4, a cytokine, was in this category. His tests showed that IL-4 was not, however, and, in fact, that NF-ΚB repressed IL-4 expression in immune system cell
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Contact: Kate O'Rourke
korourke@jhmi.edu
410-955-8665
Johns Hopkins Medical Institutions
4-Mar-2001


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