Sheryl Sinkow

BTI Professor Daniel Klessig consults with research associate Hyong Woo Choi and postdoctoral fellow Murli Manohar.

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.

A recent study led by researchers at the Boyce Thompson Institute (BTI) shows that salicylic acid, an active metabolite of aspirin, blocks HMGB1, an inflammatory protein associated with a wide variety of diseases. The finding may explain many of the drug’s therapeutic properties and offers hope that more powerful aspirin-like drugs may be developed. The research appears Sept. 23 in the journal Molecular Medicine.

“We’ve identified what we believe is a key target of aspirin’s active form in the body, salicylic acid. This protein, HMGB1, is associated with many prevalent, devastating diseases, including rheumatoid arthritis, lupus, heart disease, sepsis and inflammation-associated cancers, such as colorectal cancer and mesothelioma,” said Daniel Klessig, a professor at BTI and Cornell University.

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 Hyong Woo Choi, a research associate at BTI.

In the current study, researchers discovered the interaction between salicylic acid and HMGB1 by screening human tissue culture extracts to find proteins that bind to salicylic acid. They identified one of these proteins as HMGB1. These screens also have identified a key suspect in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, plus approximately two dozen additional candidates that have yet to be characterized.

In the body, HMGB1 normally is found inside the nucleus but can enter the bloodstream when released from injured tissues or secreted by certain immune or cancer cells. The protein in the bloodstream 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 in Milan, Italy, 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.

Klessig also teamed up with biophysicist Gaetano Montelione at Rutgers University to confirm that salicylic acid can bind to HMGB1 and to identify the binding sites.

In collaboration with Frank Schroeder, BTI associate professor, the Klessig group identified two derivatives of salicylic acid that are 50 to 1,000 times more potent than salicylic acid or aspirin at blocking HMBG1’s pro-inflammatory activities.

“Our analyses of these derivatives revealed that appropriate modifications of salicylic acid can enhance the strength of its interaction with HMGB1, providing the basis for rational design of new aspirin-like molecules,” said Montelione.

Patricia Waldron is the staff science writer for the Boyce Thompson Institute.