title: Western and Chinese antirheumatic drug-induced T cell apoptotic DNA damage uses different caspase cascades and is independent of Fas/Fas ligand interaction.
abstract: Spontaneous or therapeutic induction of T cell apoptosis plays a critical role in establishing transplantation tolerance and maintaining remission of autoimmune diseases. We investigated the mechanisms of apoptosis induced by Chinese and Western antirheumatic drugs (ARDs) in human T cells. We found that hydroxychloroquine, Tripterygium wilfordii hook F, and tetrandrine (Tet), but not methotrexate, at therapeutic concentrations can cause T cell death. In addition, Tet selectively killed T cells, especially activated T cells. Although ARD-induced cytotoxicity was mediated through apoptotic mechanisms, Fas/Fas ligand interaction was not required. We further demonstrated that the processes of phosphatidylserine externalization and DNA damage along the ARD-induced T cell apoptotic pathway could operate independently, and that selective inhibition of DNA damage by caspase inhibitors did not prevent T cells from undergoing cell death. Moreover, we found that Tet- and Tripterygium wilfordii hook F-induced T cell DNA damage required caspase-3 activity, and hydroxychloroquine-induced T cell DNA damage was mediated through a caspase-3- and caspase-8-independent, but Z-Asp-Glu-Val-Asp-fluomethyl ketone-sensitive, signaling pathway. Finally, the observation that ARD-induced activation of caspase-3 in both Fas-sensitive and Fas-resistant Jurkat T cells indicates that Fas/Fas ligand interaction plays no role in ARD-induced T cell apoptosis. Our observations provide new information about the complex apoptotic mechanisms of ARDs, and have implications for combining Western and Chinese ARDs that have different immunomodulatory mechanisms in the therapy of autoimmune diseases and transplantation rejection.
authors.affiliation: Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan, Republic of China. haungben@tpts5.seed.net.tw
authors.forename: J H
authors.initials: JH
authors.lastname: Lai
authors.forename: L J
authors.initials: LJ
authors.lastname: Ho
authors.forename: K C
authors.initials: KC
authors.lastname: Lu
authors.forename: D M
authors.initials: DM
authors.lastname: Chang
authors.forename: M F
authors.initials: MF
authors.lastname: Shaio
authors.forename: S H
authors.initials: SH
authors.lastname: Han
mesh_terms: D000470:Alkaloids / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D044182:Benzylisoquinolines; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage / Q000276:immunology*; D004365:Drugs, Chinese Herbal / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D006886:Hydroxychloroquine / Q000633:toxicity; D007113:Immunity, Innate / Q000187:drug effects; D019169:Jurkat Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D008727:Methotrexate / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D029757:Tripterygium; D020298:U937 Cells; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D044182:Benzylisoquinolines; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004365:Drugs, Chinese Herbal; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; C009438:tetrandrine; D006886:Hydroxychloroquine; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D008727:Methotrexate