By 1994, aspirin was found to actually repress the activation of NF-KB, a molecular activator of cytokines, chemicals that trigger inflammation. Dr. 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-KB repressed IL-4 expression in immune system cells.
Putting the pieces of the puzzle together, Casolaro and his team embarked on a study to test the notion that aspirin might actually increase IL-4 production using T cells from healthy donor blood and culturing them in the presence of aspirin. To his surprise, aspirin significantly reduced IL-4.
"The bottom line was a paradox," he says. "We found that aspirin had the opposite effect of what we might have expected and was clearly acting in a completely novel way."
In mapping the gene responsible for the production of IL-4, they found that aspirin targets part of a complex of DNA binding proteins that form on the IL-4 promoter, the region that regulates the quantity of protein manufactured.
"Before this study, we knew that, fundamentally, aspirin had at least two pathways of action, on COX and on NF-KB. This study is the first evidence that aspirin influences IL-4, and does so via a third, novel pathway," says Casolaro.
The researchers speculate that because IL-4 favors recruitment of inflammatory cells from the blood stream, a process implicated in rheumatoid arthritis and heart disease, suppressing IL-4 with aspirin may be one reason the drug protects against both conditions.
Other authors of the study include Antonella Cianferoni, John Schroeder, Jean Kim, John Schmidt, Lawrence Lichtenstein, and Steve Georas from Johns Hopkins. - By Kate O'Rourke
The research was funded by grants from the National Institutes of Health.
Allergy Research at Johns Hopkins
[Contact: Kate O'Rourke]