title: Akt is an endogenous inhibitor toward tumor necrosis factor-related apoptosis inducing ligand-mediated apoptosis in rheumatoid synovial cells.
abstract: Akt is known to be activated in the rheumatoid synovial tissues. We examined here functional role of Akt during tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis in rheumatoid synovial cells. Rheumatoid synovial cells in vitro were rapidly committed to apoptosis in response to TRAIL in mitochondria-dependent manner whereas Akt and extracellular signal-regulated kinase (ERK) were also phosphorylated. TRAIL-mediated apoptosis in synovial cells was significantly increased through inactivation of Akt by LY294002, however, that process was not so changed by adding ERK inhibitor, PD98059. Platelet-derived growth factor (PDGF) clearly phosphorylated both Akt and ERK in synovial cells, and PDGF pretreatment markedly suppressed TRAIL-mediated synovial cell apoptosis. The use of not PD98059 but LY294002 abrogated PDGF-mediated inhibitory effect toward TRAIL-induced apoptosis in synovial cells. The above protective effect of Akt was confirmed by the use of short interfering RNA (siRNA)-directed inhibition of Akt. Our data suggest that Akt is an endogenous inhibitor during TRAIL-mediated synovial cell apoptotic pathway, which may explain that synovial cells in situ of the rheumatoid synovial tissues are resistant toward apoptotic cell death in spite of death receptor expression.
authors.affiliation: The First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
authors.forename: Taiichiro
authors.initials: T
authors.lastname: Miyashita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
authors.forename: Mami
authors.initials: M
authors.lastname: Tamai
authors.forename: Yasumori
authors.initials: Y
authors.lastname: Izumi
authors.forename: Huang
authors.initials: H
authors.lastname: Mingguo
authors.forename: Fumiko
authors.initials: F
authors.lastname: Tanaka
authors.forename: Seigou
authors.initials: S
authors.lastname: Abiru
authors.forename: Koto
authors.initials: K
authors.lastname: Nakashima
authors.forename: Nozomi
authors.initials: N
authors.lastname: Iwanaga
authors.forename: Koichiro
authors.initials: K
authors.lastname: Aratake
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamachi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ida
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
authors.forename: Tomoki
authors.initials: T
authors.lastname: Origuchi
authors.forename: Shuzo
authors.initials: S
authors.lastname: Tagashira
authors.forename: Fumio
authors.initials: F
authors.lastname: Nishikaku
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D013722:Teprotide; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002867:Chromones; D008562:Membrane Glycoproteins; D009025:Morpholines; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D013722:Teprotide; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases