Collateral Damage pg. 4
Within the last few years, several drugs that shut off TNF-alpha signaling have come to market for the treatment of rheumatoid arthritis and other chronic inflammatory disorders such as Crohn’s disease. Since TNF-alpha signaling appears to be altered in a number of other inflammatory conditions, including cancer, multiple sclerosis and diabetes, the impact of these drugs may be far-reaching.
Stopping the cytokine storm
Cytokines are not the only chemical messengers involved in inflammation. Chemokines and cell adhesion molecules help attract and direct the “first responders” to the source of injury or infection, and to bring in the reinforcements once the inflammatory response has begun.
These factors aren’t always around, however. “They have to be produced on demand—just in time when you have inflammation,” says Hawiger, the Oswald T. Avery Distinguished Professor of Microbiology and Immunology at Vanderbilt and chair of the department.
To provide inflammatory signals only “as needed,” the genes that express them must be switched on and off. This realization has led Hawiger and his colleagues to the nucleus where, ultimately, inflammation begins.
The gene switch is operated by “stress-responsive transcription factors,” proteins that—upon activation by pro-inflammatory stimuli such as oxidative stress—slip into the nucleus and turn on the genes for inflammatory cytokines, chemokines and the like.
Hawiger’s group has developed a peptide or protein fragment called cSN50 that can keep the transcription factors out of the nucleus. This brings production of inflammatory messengers—what is commonly called the “cytokine storm”—to a screeching halt.
Recently they tested cSN50 in mice exposed to a bacterial toxin that can cause a life-threatening systemic inflammatory response called toxic shock. By shutting down cytokine and chemokine production, the peptide dramatically reduced liver damage and mortality, they reported in April.
The genomic approach may have broad implications, since excessive cytokine and chemokine production is a central theme in every inflammatory disease. About 250 genes that mediate inflammation have been identified so far. That’s just the tip of the iceberg, Hawiger says.
In 2001, a multidisciplinary group of Vanderbilt researchers led by Hawiger was formed to find genes that mediate inflammation, with the ultimate goal of identifying new targets for anti-inflammatory drugs. Funded by a $10 million grant from the National Heart, Lung and Blood Institute, the “Functional Genomics of Inflammation” program so far has developed a number of tools—including gene arrays, bioinformatics techniques and “knockout” mice—to aid in the search for the “inflamed gene.”
“We are currently pursuing between eight and 12 genes,” Hawiger says. The scientists plan to characterize the proteins expressed by these genes using proteomics techniques to determine their precise roles in inflammation.
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