title: Thalidomide induces apoptosis in human monocytes by using a cytochrome c-dependent pathway.
abstract: Thalidomide has been shown to be an effective treatment in various immunologic diseases such as Crohn's disease and rheumatoid arthritis. Its major effect is thought to be mediated by the inhibition of TNF-alpha, but the exact mechanism of action is still uncertain. Recent observations could demonstrate that the induction of monocyte apoptosis is a common feature of a variety of anti-inflammatory agents. Therefore, we investigated the role of thalidomide on monocyte apoptosis. Treatment with thalidomide resulted in apoptosis of human peripheral blood monocytes in a time- and dose-dependent manner as demonstrated by annexin V staining. Monocyte apoptosis required the activation of caspases, as combined stimulation by thalidomide together with the broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone markedly prevented monocyte cell death. Apoptosis was triggered by a CD95/CD95 ligand, TNF-RI, and TRAIL-R1 independent pathway with an inhibition of AKT-1 kinase and consecutive mitochondrial release of cytochrome c, followed by the proteolytic activation of initiator caspase-9 and effector caspase-3. Our data suggest that thalidomide-induced monocyte apoptosis is at least partially mediated by a mitochondrial signaling pathway and might contribute to the complex immunomodulatory properties of the drug.
authors.affiliation: Department of Medicine B, University of Münster, Muenster, Germany.
authors.forename: Henning R
authors.initials: HR
authors.lastname: Gockel
authors.forename: Andreas
authors.initials: A
authors.lastname: Lügering
authors.forename: Jan
authors.initials: J
authors.lastname: Heidemann
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.forename: Wolfram
authors.initials: W
authors.lastname: Domschke
authors.forename: Torsten
authors.initials: T
authors.lastname: Kucharzik
authors.forename: Norbert
authors.initials: N
authors.lastname: Lügering
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053453:Caspase 9; D020169:Caspases; D045304:Cytochromes c; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D013792:Thalidomide; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505661:FASLG protein, human; C505653:TNFSF10 protein, human; C494918:AKT1 protein, human; C506433:CASP9 protein, human