Snipping Inflammation In The Bud; New Agents May Provide Relief

First Published March 2000

MADISON - Trying a new approach to controlling the process of inflammation, scientists have forged a new class of synthetic molecules that offer a new strategy for treating pain, swelling and the other hallmarks of injury or illness.

Writing this week (March 5) in the scientific journal Nature, University of Wisconsin-Madison chemist Laura L. Kiessling describes a new family of compounds that packs a novel one-two punch that effectively inhibits the cellular processes that cause us pain.

Inflammation is the body's response to irritation, infection or injury. It begins at the level of the cell when, in response to an injury or irritation, white blood cells in the bloodstream begin to stick to the cells lining the blood vessel wall. The end result of this process is inflammation and pain.

The cells stick together with the aid of a protein called L-selectin that, with many other proteins, populates the surface of cells.

"L-selectin helps mediate an inflammatory response by binding to the carbohydrate groups attached to protein molecules on the surface of an opposing cell," said Kiessling. "The many copies of L-selectin on the white blood cell surface bind with the many copies of the L-selectin-binding protein on the blood vessel, much like fingers fitting into a glove. The inflammatory response depends on the cells sticking together."

The traditional approach to controlling inflammation, through popular over-the-counter drugs such as ibuprofen, is to block events inside the cell. The synthetic molecules in Kiessling's approach act as inhibitors on the outside of the cell, attaching themselves to a L-selectin proteins and preventing the cell from linking with an opposing cell.

But synthetic molecules that only inhibit cells from linking up have to compete with the natural cell surface proteins involved in the cell-docking process, and they don't always win. The process is also reversible. The synthetic molecules, for example, can slip off their cellular targets and the L-selectin proteins can come back into play.

However, the new class of agents developed by Kiessling and colleagues Eva J. Gordon and William J. Sanders, dubbed "neoglycopolymers," also cause cells to shed the surface protein L-selectin and that prevents the cells from docking with each other.

"It's a completely different strategy," said Kiessling. "It's like doing surgery on a really small part of the cell's surface. We're removing a protein that facilitates an unwanted inflammatory response. One advantage of this strategy is that it's not reversible, so cells no longer adhere."

The neoglycopolymers work by causing the L-selectin proteins to bunch up on the cell's surface. This activates an enzyme within the cell that, like a chemical scissors, snips the L-selectin proteins from the cell surface.

When L-selectin is lost from the cell surface, the cell's docking mechanism is no longer available, and the sheared L-selectin proteins are turned loose in the bloodstream. There, the shed protein can attach themselves to the L-selectin-binding proteins on other cells, thereby acting as inhibitors to deter the inflammation response.

Does this mean an end to pain? No, said Kiessling, but the new agents suggest new ways to design far more effective tools than those now deployed in the multi-billion-dollar fight against inflammation.

Kiessling's group is now investigating whether this novel approach to removing L-selectin has potential implications for controlling other problematic proteins on the cell surface.

"We're trying to see how general the approach is and we're trying to find the enzyme that cuts L-selectin from the cell so that we can understand more about the process.

The work of Kiessling's group was funded by the National Institutes of Health and the Mizutani Glycoscience Foundation.