A Clue to Aspirin's Benefits

By Jane Farrell

Why is aspirin so good at fighting disease? Researchers have found that it targets an inflammatory protein associated with a wide variety of illnesses. The discovery could pave the way for the development of more powerful aspirin-like drugs.

Aspirin is one of the oldest and most commonly used medicines, but many of its beneficial health effects have been hard for scientists and physicians to explain. The recent study conducted by researchers at the Boyce Thompson Institute (BTI), in collaboration with colleagues at Rutgers University and San Raffaele University and Research Institute, shows that aspirin’s main breakdown product, salicylic acid, blocks the inflammatory protein HMGB1. The blocking action may explain many of the drug’s therapeutic properties.

The findings published in the journal Molecular Medicine.

“HMGB1 is associated with many prevalent, devastating diseases in humans, including rheumatoid arthritis, heart disease, sepsis and inflammation-associated cancers, such as colorectal cancer and mesothelioma,” said senior author Daniel Klessig, a professor at BTI and Cornell University.

According to a news release from Cornell, aspirin’s pain relieving effects have long been attributed to its ability to block the enzymes cyclooxygenase 1 and 2, which produce prostaglandins—hormone-like compounds that cause inflammation and pain—a discovery that netted its discoverer, John Vane, a Nobel prize. However, the body rapidly converts aspirin to salicylic acid, which is a much less effective inhibitor of cyclooxygenase 1 and 2 than aspirin. Nonetheless, it has similar pharmacological effects as aspirin, suggesting that salicylic acid may interact with additional proteins.

“Some scientists have suggested that salicylic acid should be called ‘vitamin S’, due to its tremendous beneficial effects on human health, and I concur,” said lead author Hyong Woo Choi, a research associate at BTI.

In the current study, researchers discovered the interaction between salicylic acid and HMGB1 by screening extracts prepared from human tissue culture cells to find proteins that could bind to salicylic acid. They identified one of these proteins as HMGB1.

In the body, HMGB1 is normally found inside the nucleus, but can enter the blood stream when released from injured tissues or secreted by certain immune or cancer cells. The protein in the blood stream triggers inflammation by recruiting immune cells involved in preventing infections and repairing damaged tissues. HMGB1 also activates these recruited immune cells to express genes that code for pro-inflammatory cell-signaling proteins called cytokines.

To further investigate the interactions between salicylic acid and HMGB1’s role in the body, Klessig worked with Marco Bianchi of San Raffaele University and Research Institute, who initially discovered that HMGB1 is a trigger of inflammation. Using assays that measured the effects of salicylic acid on the recruitment and activation of immune cells, they showed that salicylic acid could block both of these functions at concentrations similar to those found in people on low-dose aspirin.

“We’ve found that HMGB1 is involved in countless situations where the body confronts damage to its own cells, which occur in many disease conditions. In retrospect, it’s almost obvious that a very general anti-inflammatory compound blocks a very general inflammation trigger,” said Bianchi.