Gatekeeper Involved In Chronic Inflammatory Diseases Identified By U Of Penn Researchers

The road to many an inflammatory disease is guarded by a cytokine messenger protein called interleukin-27, according to researchers from the University of Pennsylvania School of Veterinary Medicine. Chronic inflammation results when the immune system becomes over stimulated and begins attacking healthy tissue in excess. The Penn researchers found that IL-27 inhibits the immune system cells that are responsible for an array of inflammatory-related diseases, including encephalitis, arthritis, Crohn's disease, lupus and even sepsis.



The findings, which appear online at Nature Immunology, determine that IL-27 may be a useful target for treating a number of such autoimmune diseases. Restoring or augmenting the abilities of IL-27 may be enough to halt inflammation.



"There are many immune-mediated diseases with many different causes, but the type of cells that IL-27 inhibits are a major part of the pathway of cellular signals that lead to inflammation," said Christopher Hunter, professor in Penn Vet's Department of Pathobiology. "Our findings indicate that IL-27 is a prominent factor that helps keep the immune system under control." In previous studies, the researchers found that the IL-27 cytokine limits the duration and intensity of white blood activation, an "off switch" to the cascade of messenger proteins that serve to further activate the immune system. Prior to their research, the general assumption among scientists was that IL-27 promoted inflammation.



To understand the role of IL-27 in chronic inflammation, Hunter and his colleagues at the Ludwig Institute in Melbourne, Amgen and the NIH studied mice engineered to lack the receptor that enables IL-27 to function in normal mice. When infected with the parasite Toxoplasma gondii, which causes toxoplasmosis, the mice developed severe brain inflammation that was caused by helper T cells, a type of white blood cell that activates and directs portions of the immune system. Without the ability of IL-27 to regulate the immune system, however, the response to the infection in the brain goes out of control.



Hunter and his colleagues determined that IL-27 targets a novel subset of helper T cells, called helper T-17 cells, which previous studies from the DNAX research group in California have implicated in autoimmune disease. In healthy immune systems, inflammation is an important part of the response to infection.



According to Jason Stumhofer, a post-doctoral researcher at Penn Vet and lead author of this study, the experiment illustrates a common disease scenario in which a normal functioning part of the immune system continues to perform its task without regulation.



"Without IL-27, other brakes in the system are not sufficient to keep inflammation in check," Stumhofer said. "The more we understand the role of cytokines in the immune system, the more we realize that they are part of an elaborately balanced system kept in check by the conflicting regulatory functions of the cytokines themselves."



The findings open up the possibility that strategies that augment the effectiveness of IL-27 can be used therapeutically in these tissue specific pathologies. Perhaps the best route might be through using p28, a small active portion of the IL-27 molecule discovered by the researchers.



"It may be possible to use IL-27 or its active subunit in such a way that we can temper the immune system without suppressing the beneficial immune reactions," Hunter said.







Funding for this research was provided by the National Institutes of Health.



Contact: Greg Lester


University of Pennsylvania