Targeting inflammation

Researchers test potential therapeutic target for inflammatory disease on rheumatoid arthritis

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NEW YORK—Researchers at Hospital for Special Surgery recently published a study identifying a potential new therapeutic target in the treatment of inflammatory disorders. According to the researchers, the finding has both translational and clinical implications for diseases such as rheumatoid arthritis.

The study, published Nov. 14 in the Cell Press journal Immunity, provides new insight into how a protein called interferon gamma can increase inflammatory response. The researchers discovered a link between two molecular pathways, the Notch and Toll-like receptor pathways, which lead to the production of inflammatory proteins
or cytokines when activated. The study found that manipulating RBP-J, a protein in both pathways, could serve as a treatment for arthritis.

"Previous research has appreciated that the Toll-like receptors activate inflammatory responses and sort of activate cells to become very good at regulating the next step in immunity," says Dr. Lionel Ivashkiv, director of Basic Research at Hospital for Special Surgery. "It is also known that interferon gamma amplifies and enhances those responses, but it wasn't really understood how. What we have found is that the Notch pathway regulates a very specific part of the Toll-like receptor response and controls one subset of inflammatory response. This will allow us to fine-tune immune response in terms of both amplitude and specificity."

The researchers approached the study in a unique way—using human cells. They surveyed an entire genome to determine which genes are being expressed or which are responsible for a certain condition. Using this technology with human macrophages, white blood cells that are vital to the development of inflammatory response, they identified a subset of genes that were turned on by the activation of Toll-like receptors and inhibited by interferon gamma.

"Most studies on these kinds of systems are done with mouse models of infection," Ivashkiv says. "While there are similarities between human and animal systems, there are certain things unique to human systems and cells that are important in diseases such as rheumatoid arthritis and multiple sclerosis. We studied human cells and did signal transduction and gene expression studies to understand the mechanism that regulates these cells. We used a genetic approach to verify our data and test physiological significance."

The scientists observed that when molecules dock on the Toll-like receptors of macrophages, proteins including interleukin-6—which has been implicated in rheumatoid arthritis—are produced. In another experiment, investigators showed that the production of interleukin-6 was decreased if a protein called RBP-J was not present. Investigators also found that interfering with the production of RBP-J decreased the activation of certain Notch target genes.

Gamma secretase inhibitors that hit this new target are actually in trials for the treatment of another disease, leukemia. Ivashkiv says the researchers will look for a different use of these gamma secretase inhibitors in rheumatoid arthritis. If successful, they could probe their effectiveness in other chronic inflammatory diseases such as multiple sclerosis and artherocsclerosis.

"Current treatments inhibit everything, so the disease gets everything, and the patient becomes more susceptible to infections," Ivashkiv says. "You face various pathogens in terms of infection, so you want to have a focused response in dealing with the pathogens. You want to focus treatments on the parts of the inflammatory response that are important and specific for that disease. That's where our technology office is trying to go."

The scientists' unique approach will define the future direction of its laboratory research, Ivaskhiv says.

"Getting samples from patients with rheumatoid arthritis is the true test of the significance of our findings," Ivashkiv says. "It's great if it works in a mouse, but it's more important if the pathway is disregulated in human disease."

The study, Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-Gamma Pathways, was supported by grants from the Arthritis Foundation and the National Institutes of Health. Other authors involved in the study were Xiaoyu Hu, Allen Y. Chung, Jong Dae Ji and Indira Wu from Hospital for Special Surgery; Julia Fold and Janice Chen from the Weill Cornell Graduate School of Medical Sciences; Tomoko Tateya and Ryoichiro Kageyama from Kyoto University; Young Jun Kang and Jiahuai Han from the Scripps Research Institute; and Manfred Gessler from the University of Wurzburg. DDN

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