title: Inhibitor of apoptosis proteins as novel targets in inflammatory processes.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Munich Center for System-Based Drug Research, Department of Pharmacy, University of Munich, Germany.
authors.forename: Bettina A
authors.initials: BA
authors.lastname: Mayer
authors.forename: Markus
authors.initials: M
authors.lastname: Rehberg
authors.forename: Annette
authors.initials: A
authors.lastname: Erhardt
authors.forename: Alexander
authors.initials: A
authors.lastname: Wolf
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Reichel
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
authors.forename: Fritz
authors.initials: F
authors.lastname: Krombach
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Robert
authors.initials: R
authors.lastname: Fürst
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D003208:Concanavalin A; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012710:Serum Albumin, Bovine; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048015:TNF Receptor-Associated Factor 5 / Q000378:metabolism; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000893:Anti-Inflammatory Agents; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D020169:Caspases; D003208:Concanavalin A; D051034:Inhibitor of Apoptosis Proteins; D018799:Intercellular Adhesion Molecule-1; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D012710:Serum Albumin, Bovine; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C029180:methylated bovine serum albumin; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human