WORK ON THE BIOLOGY OF INFLAMMATION PRESENTED BY SKIN DISEASE RESEARCH CENTER INVESTIGATORS

May 20, 1996
Media Contact: Sarah Goodwin, 404/727-3366, sgoodwi@emory.edu Kathi Ovnic, 404/727-9371, covnic@emory.edu http://www.emory.edu/WHSC/

Just as the body mobilizes inflammatory processes to heal a cut finger, so too, does the body mobilize the immune system in response to internal damage, such as damage or threat perceived by human dermal microvascular endothelial cells (HDMECs) that line small blood vessels. The Skin Disease Research Center at the Emory University School of Medicine, directed by S. Wright Caughman, M.D., is a major center focusing heavily on HDMECs and their relation to the initiation of inflammatory processes. During inflammatory responses, cytokines such as tumor necrosis factor-a (TNF-a) are mobilized. These cytokines provide a signal to HDMECs to express adhesion molecules (sticky) proteins which serve as adhesion points for circulating leukocytes (white blood cells) to the site of inflammation. These processes are critical for mounting proper responses to injury or threat and are required for healing. The Emory researchers are hoping to understand the nature of the molecular signals which initiate and perpetuate inflammation. Often these processes continue inappropriately and lead to chronic inflammatory diseases such as arthritis and dermatitis. In addition, these same processes appear to be involved in the initial events leading to atherosclerosis. By understanding these molecular signals, it is hoped that therapeutic approaches can be devised which interrupt early and chronic inflammatory processes. The group recently presented the following related to this work in progress: Dr. Caughman and co-workers presented April 16 at the Experimental Biology meeting in Washington, D.C., the paper Flanking Sequences for the ICAM-1 NF-kB Response Element are Necessary for TNF-a induced Gene Expression. In it they describe the identification of a region of the ICAM-1 gene which is essentially "turned on" by the cytokine TNF-a. "Mutational analysis demonstrates that specific 5'- and 3'- flanking sequences surrounding this NF-kB binding site are necessary for TNF-a-mediated induction of ICAM-1 transcription in human microvascular endothelial cells," the authors report. They believe they have demonstrated that additional nuclear proteins are involved in the cytokine signaling process that leads to inflammation and the early migration of leukocytes to sites of injury. "Demonstration of the presence of such a protein means we've identified another target for therapies to inhibit the processes which initiate inappropriate injury, regardless of the tissue involved," Dr. Caughman says. In addition, the group presented Isolation of Immediate Early TNF-a Responsive Genes from Human Dermal Microvascular Endothelial Cell. The researchers have begun to identify and clone previously uncharacterized genes involved very early in the biologic and pathologic processes that are triggered by cytokines such as TNF-a in HDMEC and other endothelial cells. These studies provide the basis for understanding further the scope of responses, and potential targets for therapeutic intervention, that lead to localized inflammation and tissue injury, Dr. Caughman says.

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