Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction

Lai, Jenn‐Haung; Lu, K S; Chang, Deh‐Ming; Shaio, Men‐Fang; Han, Shou‐Hwa

doi:10.4049/jimmunol.166.11.6914

Cited by 47 publications

(34 citation statements)

References 82 publications

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“…Residual T cell activity can be controlled by apoptosis, and T cell apoptosis inducers have great potential for the treatment of autoimmune diseases and allograft rejection (14, 19, 48 -50). Many drugs currently used for rheumatoid arthritis and transplantation rejection kill leukocytes, including T cells, macrophages, and monocytes (14,19,48). In our study RosA selectively killed Jurkat T cells in an Lck-dependent manner.…”

Section: Discussionmentioning

confidence: 76%

Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction

Hur¹,

Yun

Won³

2004

The Journal of Immunology

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Apoptosis is one way of controlling immune responses, and a variety of immunosuppressive drugs suppress harmful immune responses by inducing apoptosis of lymphocytes. In this study we observed that rosmarinic acid, a secondary metabolite of herbal plants, induced apoptosis in an p56lck (Lck)-dependent manner; Lck+ Jurkat T cells undergo apoptosis in response to rosmarinic acid (RosA) treatment, whereas Lck− Jurkat subclone J.CaM1.6 cells do not. J.CaM1.6 cells with various Lck mutants indicated that Lck SH2 domain, but not Lck kinase activity, was required for RosA-induced apoptosis. RosA induced apoptosis in the absence of a TCR stimulus, and this was not prevented by interruption of the Fas/Fas ligand interaction. Instead, RosA-mediated apoptosis involved a mitochondrial pathway as indicated by cytochrome c release and the complete blockage of apoptosis by an inhibitor of mitochondrial membrane depolarization. Both caspase-3 and -8 were indispensable in RosA-induced apoptosis and work downstream of mitochondria and caspase-9 in the order of caspase-9/caspase-3/caspase-8. In freshly isolated human PBMC, RosA specifically induced apoptosis of Lck+ subsets such as T and NK cells, but not Lck-deficient cells, including B cells and monocytes. Moreover, RosA’s ability to kill T and NK cells was restricted to actively proliferating cells, but not to resting cells. In conclusion, Lck-dependent apoptotic activity may make RosA an attractive therapeutic tool for the treatment of diseases in which T cell apoptosis is beneficial.

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Section: Discussionmentioning

confidence: 76%

Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction

Hur¹,

Yun

Won³

2004

The Journal of Immunology

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“…To address this issue, we took advantage of the lysosomotropic amine hydroxychloroquine, which is clinically used for the treatment of malaria, rheumatoid arthritis, and systemic lupus erythematosus. As do other immunosuppressive drugs, this agent exerts potent cytotoxic effects (Lai et al, 2001), which in part may explain unwarranted effects on the nervous system and the retina (Zaidi et al, 2001;Marmor et al, 2002). Here we report that hydroxychloroquine (HCQ) induces cell death apoptosis through a lysosomal mechanism.…”

Section: Introductionmentioning

confidence: 86%

Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine

et al. 2003

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Hydroxychloroquine (HCQ) is a lysosomotropic amine with cytotoxic properties. Here, we show that HCQ induces signs of lysosomal membrane permeabilization (LMP), such as the decrease in the lysosomal pH gradient and the release of cathepsin B from the lysosomal lumen, followed by signs of apoptosis including caspase activation, phosphatidylserine exposure, and chromatin condensation with DNA loss. HCQ also induces mitochondrial membrane permeabilization (MMP), as indicated by the insertion of Bax into mitochondrial membranes, the conformational activation of Bax within mitochondria, the release of cytochrome c from mitochondria, and the loss of the mitochondrial transmembrane potential. To determine the molecular order among these events, we introduced inhibitors of LMP (bafilomycin A 1 ), MMP (Bcl-X L , wild-type Bcl-2, mitochondrion-targeted Bcl-2, or viral mitochondrial inhibitor of apoptosis from cytomegalovirus), and caspases (Z-VAD.fmk) into the system. Our data indicate that caspase-independent MMP is rate-limiting for LMP-mediated caspase activation. Mouse embryonic fibroblasts lacking the expression of both Bax and Bak are resistant against hydroxychloroquine-induced apoptosis. Such Bax À/À Bak À/À cells manifest normal LMP, yet fail to undergo MMP and subsequent cell death. The data reported herein indicate that LMP does not suffice to trigger caspase activation and that Bax/Bak-dependent MMP is a critical step of LMP-induced cell death.

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“…The apoptotic process involves the activation of caspases (EC 3.4.22.36), cysteine proteases that trigger a series of reactions leading to DNA degradation (Choi et al, 2003). Defects in the apoptotic process, particularly in T cells, may be involved in autoimmune diseases (Lai et al, 2001;Ho and Lai, 2004). Induction of apoptosis in T or B cells, or inhibition of their proliferation, reduces inflammation triggered by these cells (Ho and Lai, 2004).…”

Section: Adhesion and Surface Molecules-amongmentioning

confidence: 99%

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

et al. 2007

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Plants in the genus Tripterygium, such as Tripterygium wilfordii Hook. f., have a long history of use in traditional Chinese medicine. In recent years there has been considerable interest in the use of Tripterygium extracts and of the main bioactive constituent, the diterpene triepoxide triptolide (1), to treat a variety of autoimmune and inflammation-related conditions. The main mode of action of the Tripterygium extracts and triptolide (1) is the inhibition of expression of proinflammatory genes such as those for interleukin-2 (IL-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interferon-gamma (IFN-γ). The efficacy and safety of certain types of Tripterygium extracts were confirmed in human clinical trials in the US and abroad. Over 300 compounds have been identified in the genus Tripterygium, and many of these have been evaluated for biological activity. The overall activity of the extract is based on the interaction between its components. Therefore, the safety and efficacy of the extract cannot be fully mimicked by any individual constituent. This review discusses the biochemical composition and biological and pharmacological activities of Tripterygium extracts, and their main bioactive components.

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Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction

Cited by 47 publications

References 82 publications

Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction

Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction

Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

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