title: New disease-modifying antirheumatic drug 2 acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298) selectively augments activation-induced T cell death.
abstract: We examined in this study whether the newly developed disease-modifying antirheumatic drug (DMARD) 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298) augments activation-induced T cell death. Peripheral blood (PB) T cells, isolated from healthy donors, were activated by incubation with interleukin-2 (IL-2) followed by further culture with 12-0-tetradecanoyl phorbol 13-acetate (PMA) and ionomycin in the presence or absence of KE-298. The apoptosis of activated T cells was examined by flow cytometric determination of hypodiploid DNA. Fas expression and caspase-3 activity in activated T cells were also examined by flow cytometry, and expression of Fas ligand (FasL), Bcl-2-related proteins, and X chromosome-linked inhibitor of apoptosis protein (XIAP) was determined by Western blot analysis. Apoptosis was not obvious in resting T cells and was not augmented by KE-298. In contrast, apoptosis was clearly detected in activated T cells (activation-induced T cell death) with the increment of caspase-3 activity, and incubation of these cells with KE-298 further enhanced apoptosis. Treatment of activated T cells with KE-298 increased Bax expression but decreased XIAP expression without affecting the expression of Fas/FasL. Thus caspase-3 activity in activated T cells appeared to be increased by KE-298. Our results suggest that the newly developed DMARD, KE-298, selectively augmented activation-induced T cell death. This finding may contribute to the therapeutic efficacy of KE-298 in rheumatoid arthritis (RA) patients and provide new insight into the pharmacologic action of DMARDs.
authors: First Department of Internal Medicine and the Department of Hospital Pharmacy, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
authors: S
authors: S
authors: Urayama
authors: A
authors: A
authors: Kawakami
authors: T
authors: T
authors: Nakashima
authors: S
authors: S
authors: Yamasaki
authors: A
authors: A
authors: Hida
authors: H
authors: H
authors: Ida
authors: M
authors: M
authors: Kamachi
authors: H
authors: H
authors: Nakamura
authors: T
authors: T
authors: Origuchi
authors: K
authors: K
authors: Migita
authors: Y
authors: Y
authors: Kawabe
authors: K
authors: K
authors: Eguchi
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology*; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D019014:fas Receptor / Q000032:analysis / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; C494811:BCL2L1 protein, human; D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D010666:Phenylpropionates; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C108637:aspartyl-glutamyl-valyl-aspartal; D051020:bcl-X Protein; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C078547:esonarimod