Inhibitor of Apoptosis Proteins as Novel Targets in Inflammatory Processes
| Autor: | Robert Fürst, Stefan Zahler, Fritz Krombach, Alexander Wolf, Markus Rehberg, Angelika M. Vollmar, Gisa Tiegs, Bettina A. Mayer, Annette Erhardt, Christoph A. Reichel, Michael Kracht |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Time Factors Anti-Inflammatory Agents Apoptosis p38 Mitogen-Activated Protein Kinases Inhibitor of Apoptosis Proteins Mice Concanavalin A Leukocytes NF-kappa B Serum Albumin Bovine Intercellular Adhesion Molecule-1 MAP Kinase Kinase Kinases Baculoviral IAP Repeat-Containing 3 Protein XIAP Cell biology Caspases RNA Interference Tumor necrosis factor alpha Chemical and Drug Induced Liver Injury biological phenomena cell phenomena and immunity medicine.symptom Cardiology and Cardiovascular Medicine musculoskeletal diseases Proteasome Endopeptidase Complex Ubiquitin-Protein Ligases Inflammation Biology Transfection Inhibitor of apoptosis Downregulation and upregulation Cell Adhesion medicine Animals Humans TNF Receptor-Associated Factor 5 Dose-Response Relationship Drug MAP kinase kinase kinase Tumor Necrosis Factor-alpha JNK Mitogen-Activated Protein Kinases Transendothelial and Transepithelial Migration Ubiquitination Endothelial Cells TNF Receptor-Associated Factor 2 Arthritis Experimental Enzyme Activation Mice Inbred C57BL body regions Disease Models Animal Endothelium Pharmacology NF-kappaB inflammation inhibitor of apoptosis proteins (IAPs) Protein Processing Post-Translational HeLa Cells |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 31:2240-2250 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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