Chronic localized inflammation characterizes many disease states including asthma and arthritis, and is very difficult to treat effectively. A team of investigators led by Privatdozent Robert Fürst and Professor Angelika Vollmar of the Center for System-Based Drug Research at LMU has now identified a new class of anti-inflammatory agents. These compounds target so-called IAP proteins, which were previously known primarily for their function as regulators of programmed cell death. Fürst‘s group has now shown that IAPs also play an important role in promoting inflammation. Inhibition of IAP action reduces inflammation by preventing infiltration of immune cells from the bloodstream into the affected tissues. IAPs therefore provide a promising target for the design of new anti-inflammatory drugs.
Programmed cell death – otherwise known as apoptosis – is an inducible self-destruct program initiated by diseased or damaged cells, which serves to protect the integrity of the organism as a whole. Among the factors that regulate this process are the “inhibitors of apoptosis” (IAPs). As their name implies, these proteins block execution of the cellular suicide program. Tumor cells express high levels of IAPs, making them less susceptible to programed cell death and enabling their continued proliferation. For this reason, IAPs are of particular interest to researchers seeking new drug targets for the development of innovative anti-tumor therapies. Indeed, several compounds have already been synthesized that inhibit the action of IAPs and are now undergoing preclinical and clinical tests.
“Interestingly, many of the signal pathways that are induced in tumor cells are also active in cells involved in the inflammation process. We therefore suspected that IAPs might have an important role to play not only in malignancy but also in inflammation,” says Dr. Bettina Mayer, who is first author on the new study. The researchers used animal models to test their idea, focusing on the question of whether inhibitors of IAPs could be employed effectively to treat conditions associated with chronic inflammation. “There is a continuing need for new anti-inflammatory agents, because only a small number of drug types is currently available, and many of them are unsatisfactory, either because they not sufficiently potent or have serious side-effects,” explains Fürst.
The new study looked at two experimental models in mice, one for arthritis of the knee and the other for hepatitis. In both systems they found that an IAP inhibitor indeed reduced levels of inflammation. They went on to show that this is mainly due to its effect on IAP activity in cells of the endothelium, which lines the blood vessel wall. To reach the tissues, immune cells must pass through this barrier. This requires that they first to bind to the endothelial cells. It emerged that the IAP inhibitor prevents them from doing so by blocking the expression of specific adhesion molecules on the endothelial cell surface. “IAP inhibitors therefore represent an entirely new class of therapeutic agent for the treatment of inflammatory conditions, and could provide a basis for the development of new treatments for inflammatory states,” says Mayer. (göd/PH)
Inhibitor of Apoptosis Proteins as Novel Targets in Inflammatory Processes.
B. A. Mayer, M. Rehberg, A. Erhardt, A. Wolf, C. A. Reichel, M. Kracht, F. Krombach, G. Tiegs, S. Zahler, A. M. Vollmar, R. Fürst.
Arterioscler Thromb Vasc Biol 2011, 31:2240-2250.
PD Dr. Robert Fürst
Department Pharmazie – Zentrum für Pharmaforschung
Lehrstuhl Prof. Dr. Angelika Vollmar
Phone: 089 2180-77189
Fax: 089 2180-77170