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"The Proof is in the Process"

PCOM Researchers Delve Deep into the Wide World of Inflammation

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."

The researchers

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.

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Dr. Gorski is interested in locating genetic differences between patients who have RA or other inflammatory diseases such as lupus (SLE - systemic lupus erythematosus) and those who do not have the disease. "These gene differences might, at least partially, explain an RA patient's inability to 'turn off' the cascading inflammatory process," notes Dr. Gorski. "It could also explain why some people have the disease while others don't." Another project of Dr. Borghaei's also examines a polymorphism in the MMP-3 gene that affects the ability of NFkB to repress MMP-3 production.

Dr. Daghigh is studying the effects of nitric oxide (NO), a free radical generated in biological systems. "NO functions at low levels as a signal in diverse physiological processes, such as blood pressure control, neurotransmission, learning, memory and many others," Dr. Daghigh explains. "Excessive NO generated from the enzyme inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of inflammatory diseases." Dr. Daghigh has been able to show that human gingival fibroblasts (from patients with periodontitis) are a source of NO. Recent results from her research indicate that cytokines stimulate iNOS to produce large amounts of NO. This work has been accepted for publication in the Journal of Periodontology.

Dr. Thornton has taken a wider view of inflammation by searching for genes that are stimulated by the proinflammatory cytokine IL-1. Among the many genes she found to be upregulated by IL-1, most, as

expected, participated in destructive functions. However, several also had constructive functions, such as bone morphogenetic protein (BMP-2), which helps to build bone, the opposite of MMP action. This work was done with Martin J. Fowler, DO '00, when he was a graduate student in the department. "My work is focused right now on hypoxia inducible factor-1 (HIF-1), a transcription factor which 'turns on' other genes potentially important in the inflammatory process," notes Dr. Thornton. "HIF-1, as its name suggests, is known to be controlled by hypoxia [when cells don't have enough oxygen], but this form of regulation by cytokines is new."

Are Dr. Thornton and other researchers in biochemistry/ molecular biology looking for a cure for RA and periodontitis?  Yes, with an eye toward the basic cause, and an understanding that broadening their knowledge of the process leads to finding ways to stop the effects of disease or to eliminate it altogether.  "Scientists learned about HIV in this manner," points out Dr. Borghaei. "Some people were studying retroviruses for a time, then HIV happened and some of the pieces of the puzzle were already in place. Everyone wants to do research with the goal of a cure, but how things work has value in and of itself. It's about the process," she emphasizes, echoing a familiar theme in the department of biochemistry/molecular biology. "How do you hope to eventually arrive at a cure if you don't understand the process?"

This article appeared in the DIGEST, 2002 No.1, as one in a series of articles on research at PCOM.