Key Pathway, Potential Drug Targets in Autoinflammatory Disease Identified

by VR Sreeraman on  November 13, 2007 at 7:37 PM Research News   - G J E 4
Key Pathway, Potential Drug Targets in Autoinflammatory Disease Identified
A recent study has found a key pathway of cellular events behind some potentially dangerous autoinflammatory diseases.

The study at Thomas Jefferson University did not only gain a greater understanding of the disease process but also determined new potential drug targets for diseases ranging from arthritis to cancer.

The authors described how two proteins called PSTPIP1 and pyrin interacted to cause autoinflammatory diseases, inherited diseases characterized by seemingly unprovoked and recurrent attacks of fever and inflammation.

The authors also discovered that autoinflammatory diseases were largely caused by the defects in proteins that regulate inflation.

According to the study, defects in pyrin were linked to familial Mediterranean fever, a sometimes fatal disease found in the Mediterranean, Middle East and Europe. While defects in PSTPIP1 were linked to a rare, autoinflammatory disease called PAPA syndrome. The two proteins apparently works together in the same inflammatory pathway, but it was difficult to identify that they would lead to diseases.

The researchers found that mutant form of PSTPIP1 found in patients with PAPA syndrome could turn on pyrin, which eventually led the activation of a potent inflammation-causing protein, IL-1 beta, which caused fever and the production of related substances.

"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," said Emad Alnemri, Ph.D., professor of Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University.

The study states the activation of these proteins turned them to become potential therapeutic targets. For example, there is a synthetic analog of the IL-1 receptor "antagonist" called Anakinra that has been successfully used in clinical trials to treat autoinflammatory diseases, including PAPA syndrome and familial Mediterranean fever, in addition to other chronic inflammatory diseases such as rheumatoid arthritis.

Dr. Alnemri explained thatt IL-1 beta binds to a receptor on the cell membrane that "induces the inflammatory phenotype" Anakinra mimics IL-1 beta and binds to the same receptor, preventing IL-1 beta from binding and consequently blocking its effects on cells. "Detailing these mechanisms is not only important for autoinflammatory disease, but for most inflammatory disease in general."

The study also finds out that chronic inflammation was linked to the development of cancer. It was also noted that IL-1 beta appears to play a major role in tumor growth. Elevated concentrations of IL-1 beta have been found in aggressive forms of colon, breast and lung cancers.

Though it was clear how IL-1 beta promoted cancer growth, but the data suggested that in addition to its ability to stimulate production of inflammatory factors, it also stimulated cells to produce angiogenic factors to enhance angiogenesis, or the development of tumor-growth promoting blood vessels.

"IL-1 beta antagonists are being tested against cancer in animal models with notable success, so you might actually be able to treat some forms of cancer by targeting proteins upstream in the inflammatory pathways, such as caspase-1, pyrin or PSTPIP1 to stop the generation of IL-1 beta," said Dr. Alnemri.

The study was published in the 'Molecular Cell' journal.

Source: ANI

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