Celsus detailed the four cardinal signs of inflammation: rubor (redness), tumor (swelling), calor (heat) and dolor (pain). Inflammation is the body's way of fighting back. Celsus was right on target. Since then, we've learned that inflammation involves many tissues and myriad chemical mediators.Ruth D. Thornton, PhD, Chair and Professor, Biochemistry/Molecular Biology and others in the department are each studying a small piece of the very large puzzle that is inflammation.
"Of the major mediators, the proinflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), are among the first on the scene," explains Dr. Thornton. These cytokines act on many different cells close to an injury site, but they also can travel through the bloodstream to distant tissues. Cytokines activate many other defensive reactions, including the production of nitric oxide and matrix metalloproteinases.
Usually, inflammation is acute and healing follows. Inflammation becomes chronic when IL-1 and TNF remain even after the initiator of inflammation has disappeared. These mediators help to establish chronic inflammation, such as that seen in rheumatoid arthritis (RA).
The researchers in the biochemistry/molecular biology department are studying what occurs just before, after and while inflammation takes hold in RA, using periodontitis as a model in some instances because it's easier to study. "Even though we can identify microbes as the cause of periodontitis, while the cause of RA is unknown, there are similarities; the nflammatory cytokines are systemic in both," notes Dr. Thornton. "What we learn from one should apply to the other, and hopefully to many other inflammatory diseases as well."
Dr. Thornton is interested in learning what IL-1 does to activate synovial cells that line the joints of people with RA. Farzaneh Daghigh, PhD, assistant professor, is studying the effects of nitric oxide, a soluble gas, on inflammatory disease. Grzegorz Gorski, MD, PhD, instructor, is interested in which genes are slightly different (have polymorphisms) in RA patients from the genes of others without RA. Ruth Carter Borghaei, PhD, associate professor, is studying the effects of inflammation on gene expression.
Dr. Borghaei's work has been continually funded by the National Institutes of Health for the past seven years. She's been taking a detailed look at the genes called matrix metalloproteinases collagenase-1 (MMP-1) and stromelysin (MMP-3). Both are significant because they are involved in normal physiological tissue remodeling as well as in a number of pathological processes, including periodontitis, RA, cancer, angiogenesis, atherosclerosis, emphysema and osteoporosis.
Dr. Borghaei's research focuses on identifying and studying mechanisms involved in transcriptional regulation of these genes in response to cytokines."The goal of my research is to identify transcription factors involved in regulating expression of MMP-1 and MMP-3 during inflammation," notes Dr. Borghaei. "We've found that a particular transcription factor, NFkB, which usually increases gene expression in response to inflammation, actually works as a repressor for MMP-3. So IL-1 increases MMP-3, but it also increases a factor that limits the increase in MMP-3. That sounds complicated, but it's kind of like having an accelerator and a brake on at the same time," she explains. "This finding is important, not only for our understanding of how the MMP-3 gene is regulated during inflammation, but it may also increase our understanding of gene regulatory mechanisms in general," adds Dr. Borghaei.