Inhibitor of Apoptosis Proteins as Novel Targets in Inflammatory Processes
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 antiinflammatory 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 5.
Conclusion—Our results reveal IAP antagonism as a profound antiinflammatory principle in vivo and highlight IAPs as important regulators of inflammatory processes in endothelial cells.
- Received November 3, 2010.
- Accepted July 21, 2011.
- © 2011 American Heart Association, Inc.