An anti-inflammatory therapy utilizing proteins called type 1 interferon IFN-alpha and IFN-beta (IFN-α/β) has been shown by researchers at the University of California, San Diego (UCSD) School of Medicine and their colleagues in Japan and Israel to offer relief in mouse models of Crohn's disease and ulcerative colitis, the two major forms of the painful, chronic condition called inflammatory bowel disease (IBD) that affects nearly 1 million Americans.
Published in the March 2005 issue of the Journal of Clinical Investigation (JCI), the study provides the first description of the molecular mechanism by which IFN-α/β inhibits the severity of colitis and maintains intestinal homeostasis, or the "constant state" of the gut, by suppressing pro-inflammatory activity by the immune system macrophages.
"Although IFN-α/β therapy has been tried in recent clinical trials, along with other anti-inflammatory treatments, researchers have not understood how or why IFN-α/β might work as an IBD treatment," said Eyal Raz, M.D., UCSD professor of medicine and the study's senior author. "Our study describes how activated IFN-α/β plays a protective role in colonic inflammation."
The study's first author, Kyoko Katakura, M.D, Department of Medicine II, Fukushima, Japan, added that the team's results point to an important protective and potential therapeutic role for IFN-α/β.
In an accompanying Commentary in the March issue of JCI, German researchers Stefan Wirtz and Markus F. Neurath noted that the results "suggest that strategies to modulate innate immunity may be of therapeutic value." They added that "It is astonishing to realize that in spite of the existence of clinical trials on the use of IFN-α/β in the treatment of UC (ulcerative colitis), there is only very limited information about their expression and biological function in the immune system of the gut."
The Raz team discovered the role of IFN-α/β through their continuing studies of an immune system molecule called Toll-like receptor 9 (TLR9). In previous research* the researchers had shown that TLR9 initiated an anti-inflammatory program to ease colitis in experimental animals. In the new study, the investigators again utilized mouse models to explore how TLR9 eases inflammation. This time, however, they found differing reactions in two strains of mice.
Agents that activate TLR9 were given to the two different groups of mice that appear similar, but are from strains that make them genetically different. The TLR9 activators given to one of the groups, called RAG mice, inhibited the severity of experimental colitis, but had no effect on the other group of mice, called SCID mice.
To understand why the mice reacted differently, the researchers used a variety of scientific approaches to explore the cellular and molecule events that caused one strain to respond to therapy and the other to be resistant. They determined that TLR9-induced protection occurs when the proteins IFN-α/β were activated. The resistance to protection in the SCID mice was due to a mutation that impairs IFN-α/β signaling in these mice. Additional experiments with mice developed without IFN-α/β further verified the proteins' role in intestinal homeostasis.
The study was funded by the National Institutes of Health. Additional authors included first author Kyoko Katakura, M.D, Department of Medicine II, Fukushima, Japan, Jongdae Lee, Ph.D., and Lars Eckmann, M.D., UCSD Department of Medicine; and Daniel Rachmilewitz, M.D., professor and head of the Division of Internal Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
* Researchers Show Beneficial Role of Bacterial DNA In Fighting Inflammatory Bowel Disease http://health.ucsd.edu/news/2002/04_29_Raz.html
* Probiotics Beneficial Even When Inactive, According to UCSD Study http://health.ucsd.edu/news/2004/02_02_Raz.html
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