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Jefferson scientists uncover key pathway, potential drug targets in autoinflammatory disease
Date:11/12/2007

(PHILADELPHIA) Molecular biologists at Jeffersons Kimmel Cancer Center in Philadelphia have detailed the cascade of cellular events behind some potentially dangerous autoinflammatory diseases. In doing so, they not only have gained a greater understanding of the disease process, but have also identified new potential drug targets for diseases ranging from arthritis to cancer.

Reporting in the journal Molecular Cell, Emad Alnemri, Ph.D., professor of Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University, and his co-workers describe how two proteins called PSTPIP1 and pyrin interact to cause autoinflammatory diseases, inherited diseases characterized by seemingly unprovoked and recurrent attacks of fever and inflammation. Such diseases have been found largely to be caused by defects in proteins that regulate inflammation.

According to Dr. Alnemri, defects in pyrin, for example, have been linked to familial Mediterranean fever, a sometimes fatal disease found in the Mediterranean, Middle East and Europe. Defects in PSTPIP1 have been linked to a rare, autoinflammatory disease called PAPA syndrome. The two proteins apparently worked together in the same inflammatory pathway, but no one understood how these proteins could lead to disease.

Dr. Alnemri and his co-workers figured out how. They found that mutant forms of PSTPIP1 found in patients with PAPA syndrome can turn on pyrin, which eventually leads to activating a potent inflammation-causing protein, IL-1 beta. Once activated, IL-1 beta can cause inflammation, fever and the production of other related substances.

Dr. Alnemri explains, Because mutant PSTPIP1 proteins interact with pyrin much more strongly than normal PSTPIP1, they cause uncontrolled or exaggerated activation of pyrin and consequently more secretion of IL-1 beta in these patients.

These proteins now become potential therapeutic targets, Dr. Alnemri says. For
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Contact: Steve Benowitz
steven.benowitz@jefferson.edu
215-955-5291
Thomas Jefferson University
Source:Eurekalert

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