Inhibitor of Apoptosis Proteins as Novel Targets in Inflammatory Processes

• DOI: 10.1161/atvbaha.111.234294
• Publication Date: 2011-08-05T04:23:23Z
• Authors: Bettina A. Mayer; Markus Rehberg; Annette Erhardt; Alexander Wolf; Christoph A. Reichel; Michael Kracht; Fritz Krombach; Gisa Tiegs; Stefan Zahler; Angelika M. Vollmar; Robert Fürst
• Keywords: 0301 basic medicine; Anti-Inflammatory Agents; Apoptosis; Inhibitor of Apoptosis Proteins; 03 medical and health sciences; Cell Adhesion; Concanavalin A; Leukocytes; Animals; Humans; Dose-Response Relationship, Drug; JNK Mitogen-Activated Protein Kinases; Endothelial Cells; Intercellular Adhesion Molecule-1; MAP Kinase Kinase Kinases; 540; Arthritis, Experimental; Baculoviral IAP Repeat-Containing 3 Protein; 3. Good health; Enzyme Activation; Disease Models, Animal; Caspases; Endothelium; Pharmacology; NF-kappaB; inflammation; inhibitor of apoptosis proteins (IAPs); Chemical and Drug Induced Liver Injury; HeLa Cells

Objective— Inhibitor of apoptosis proteins (IAPs), such as X-linked or cellular IAP 1/2 (XIAP, cIAP1/2), are important regulators of apoptosis. IAP antagonists are currently under clinical investigation as anticancer agents. Interestingly, IAPs participate in the inflammation-associated TNF receptor signaling complex and regulate NFκB signaling. This raises the question about the role of IAPs in inflammation. Here, we investigated the anti-inflammatory potential of IAP inhibitors and the role of IAPs in inflammatory processes of endothelial cells.

Methods and Results— In mice, the small molecule IAP antagonist A-4.10099.1 (ABT) suppressed antigen-induced arthritis, leukocyte infiltration in concanavalin A-evoked liver injury, and leukocyte transmigration in the TNFα-activated cremaster muscle. In vitro, we observed an attenuation of leukocyte–endothelial cell interaction by downregulation of the intercellular adhesion molecule-1. ABT did not impair NFκB signaling but decreased the TNFα-induced activation of the TGF-β–activated kinase 1, p38, and c-Jun N-terminal kinase. These effects are based on the proteasomal degradation of cIAP1/2 accompanied by an altered ratio of the levels of membrane-localized TNF receptor-associated factors 2 and 5.

Conclusion— Our results reveal IAP antagonism as a profound anti-inflammatory principle in vivo and highlight IAPs as important regulators of inflammatory processes in endothelial cells.