U Researchers Find New Role for an Old Cell...Looking at Chronic Inflamation

U Researchers Find New Role for an Old Cell...Looking at Chronic Inflamation

May 2, 2004 6:00 PM

University of Utah medical researchers have discovered a "new trick by an old cell" that may lead to treating inflammatory damage in conditions such as rheumatoid arthritis, chronic lung syndromes, and restenosis--a major complication that can arise when stents are used to help open clogged arteries.

In an article published in the April 26 online edition of the Proceedings of the National Academy of Sciences, U of U School of Medicine researchers say that neutrophils--blood cells that are crucial in the body's inflammatory response to trauma and germs--have a previously unknown mechanism of turning on a gene that contributes to chronic inflammation. The gene codes for a protein, IL-6 receptor alpha (IL6Ra), that is produced as part of the acute inflammation that occurs in response to trauma or infection. But when the production of IL-6Ra goes awry, it can cause acute inflammation to become chronic.

"This discovery gives new insights into how neutrophils can make new factors that turn on other inflammatory cells in an unregulated fashion," said Guy A. Zimmerman, M.D., professor of internal medicine, director of the University's Program in Human Molecular Biology and Genetics (HMBG) at the Eccles Institute of Human Genetics, and the study's corresponding author. "This is a new trick by an old cell."

Studied for more than 100 years, neutrophils, also called polymorphonuclear leukocytes (PMNs), are among the body's first defenders in containing bacteria and protecting wounds through acute inflammation. But, in contrast, they also cause tissue injury in a large number of acute and chronic inflammatory diseases, such as sepsis, rheumatoid arthritis, and atherosclerosis.

PMNs long have been known to store and carry proteins for rapid use. More recently they have been found to activate genes that code for other inflammatory proteins. But, the Utah researchers found, PMNs also carry in a quiescent state messenger RNAs that have the code for several important factors, including IL-6Ra. When PMNs receive biochemical signals during an inflammatory response, they turn on the pathway that produces IL-6Ra. One of the biochemical signals that triggers the pathway is platelet activating factor (PAF), an inflammatory mediator that the Utah group also has studied.

"These proteins are controlled by highly regulated genes and their production is turned on very quickly," Zimmerman said.

A number of proteins in addition to IL-6Ra are made by this pathway, and not all of them contribute to chronic inflammation. IL-6Ra is not the only gene involved in chronic inflammation, but its unregulated production plays a major role, according to the U of U researchers.

One of the most common problems involving chronic inflammation is restenosis--a process in which scar tissue forms around stents placed to unclog coronary arteries. The Utah researchers' discovery of the previously unknown pathway in neutrophils opens the possibility of finding new drugs to fight chronic inflammatory problems.

One such drug already exists. Sirolimus, also called rapamycin, is used to help prevent rejection after organ transplants. Sirolimus also shuts down the pathway in neutrophils and has been effective in preventing restenosis in recent clinical trials, according to Zimmerman. Stents coated with sirolimus now are commonly used in cardiac catheterization laboratories. The U of U researchers used it in their experiments and it completely prevented the production of IL-6Ra by blocking the newly discovered pathway.

"It's quite possible the drug is interrupting the production of proteins coded by inflammatory genes that act very early in the process," Zimmerman said.

Other researchers involved in the project, all from the University of Utah School of Medicine and Program in Human Molecular Biology and Genetics (HMBG), include Stephen W. Lindemann M.D., HMBG; Christian C. Yost, M.D., instructor of pediatrics, HMBG; Melvin Dennis, B.S., HMBG; Thomas M. McIntyre, Ph.D., professor of internal medicine; Andrew S. Weyrichu , Ph.D., research associate professor of internal medicine, HMBG.

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