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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 This information is current as of September 26, 2021. Jenn-Haung Lai, Ling-Jun Ho, Kuo-Cheng Lu, Deh-Ming Chang, Men-Fang Shaio and Shou-Hwa Han J Immunol 2001; 166:6914-6924; ; doi: 10.4049/jimmunol.166.11.6914 http://www.jimmunol.org/content/166/11/6914 Downloaded from References This article cites 86 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/166/11/6914.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction1 Jenn-Haung Lai,2*‡ Ling-Jun Ho,*‡ Kuo-Cheng Lu,† Deh-Ming Chang,* Men-Fang Shaio,§ and Shou-Hwa Han¶ Spontaneous or therapeutic induction of T cell apoptosis plays a critical role in establishing transplantation tolerance and main- taining remission of autoimmune diseases. We investigated the mechanisms of apoptosis induced by Chinese and Western anti- rheumatic 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 Downloaded from 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 path- way. Finally, the observation that ARD-induced activation of caspase-3 in both Fas-sensitive and Fas-resistant Jurkat T cells http://www.jimmunol.org/ 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. The Journal of Immunology, 2001, 166: 6914–6924. he etiology of autoimmune diseases, including rheuma- initiation and progression is triggered by T cell activation (3, 4). toid arthritis, remains largely unknown. Current therapy Therefore, most therapies target the inhibition of activated T cells for rheumatoid arthritis is aimed at attenuating disease (5, 6). T by guest on September 26, 2021 activity with a combination of disease-modifying antirheumatic In addition to the activation of T cells, defective regulation of T drugs (DMARDs),3 including methotrexate (MTX), sulfasalazine, cell apoptosis (programmed cell death) also plays a crucial role in and hydroxychloroquine (HCQ) (1, 2). Despite aggressive medical disease progression (7–9). Recent work demonstrating the require- treatment, the morbidity and mortality of rheumatoid arthritis are ment for T cell apoptosis to establish transplantation tolerance further still high. Therapy is limited by the limited understanding of patho- highlights the importance of this process (10). Apoptosis-based ther- physiologic processes underlying the illness. In this context, al- apy has been suggested as one of the approaches to controlling the though the activation of other immune effector cells such as mac- progression of autoimmune diseases (11). We and other investigators rophages, B cells, and synovial cells may participate in the process showed that the immunosuppressive effects of the Western antirheu- of joint destruction in rheumatoid arthritis, the process of disease matic drug (ARD), HCQ, and of Chinese ARDs, tetrandrine (Tet) and Tripterygium wilfordii hook F (TWHf), were mediated through both *Rheumatology/Immunology and Allergy, Department of Medicine, and †Division of the inhibition of T cell activation and the induction of T cell apoptosis Nephrology, Department of Medicine, Tri-Service General Hospital, National De- (12–15). In addition, high concentrations (0.1–10 ␮M) of MTX, fense Medical Center, Taiwan, Republic of China; ‡Graduate Institute of Life Science, another important DMARD, have been shown to induce apoptosis of National Defense Medical Center, Taiwan, Republic of China; §Department of Par- asitology and Tropical Medicine, National Defense Medical Center, Taiwan, Republic activated PBLs (16). of China; and ¶Immunology Division, Cheng-Hsin Rehabilitation Medical Center, HCQ is considered to be an agent whose immunomodulatory Taiwan, Republic of China effects are comparable to those of other DMARDs, but it is less Received for publication May 19, 2000. Accepted for publication March 22, 2001. toxic, and it is useful in combination therapy (17). TWHf (or The costs of publication of this article were defrayed in part by the payment of page Thunder God Vine, a complex herbal remedy) has been widely charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. used, with great success clinically, to treat autoimmune diseases 1 This work was supported by a grant from National Health Research Institutes, Tai- such as systemic lupus erythematosus and rheumatoid arthritis in wan, Republic of China (NHRI-GT-EX89B915C). mainland China for decades (reviewed in Refs. 18 and 19). Puri- 2 Address correspondence and reprint requests to Dr. J.-H. Lai, Rheumatology/Im- fied products from TWHf have been shown to down-regulate the munology and Allergy, Tri-Service General Hospital, No. 325, Section 2, Cheng- expression of cyclooxygenase-2, a critical molecule that is induced Kung Road, Neihu 114, Taipei, Taiwan. E-mail address: [email protected] during inflammation (20). Aside from TWHf, the plant alkaloid 3 Abbreviations used in this paper: DMARD, disease-modifying antirheumatic drugs; MTX, methotrexate; ARD, antirheumatic drug; TWHf, Tripterygium wilfordii hook Tet is another major ARD used to treat silicosis and rheumatic F; Tet, tetrandrine; HCQ, hydroxychloroquine; FasL, Fas ligand; PS, phosphatidyl- diseases in mainland China (21). The immunomodulatory effects serine; Z-VAD-fmk, Z-Val-Ala-Asp-fluomethyl ketone; Z-DEVD-fmk, Z-Asp-Glu- Val-Asp-fluomethyl ketone; LDH, lactate dehyrogenase; PI, propidium iodide; of Tet and its analogs have been demonstrated both in vitro and in FADD, Fas-associated death domain protein. vivo (22–25). Recent work from us and other investigators on Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 6915 these two Chinese ARDs provide additional support for their great Ficoll-Hypaque density gradient centrifugation. The activated T cells were potential not only in the therapy of autoimmune diseases, but also then treated with ARDs in the absence of exogenous IL-2 as described for in the prevention of transplantation rejection (14, 15, 26, 27). the resting T cells. In the present study the molecular events that mediate ARD- Measurement of nonspecific cytotoxicity induced T cell apoptosis were examined. Our results demonstrate Several assays were used to examine drug toxicity in human peripheral that ARD-induced T cell apoptosis was not dependent on Fas/Fas blood T cells and different human cell lines. The release of lactate dehy- ligand (FasL) interaction. Interestingly, ARD-induced DNA dam- drogenase (LDH) as an indicator of damage to the plasma membrane and age and phosphatidylserine (PS) externalization were indepen- cell death was measured according to the manufacturer’s instructions dently regulated, and selective prevention of DNA damage by (Roche, Indianapolis, IN). The percent cytotoxicity was calculated as (sam- Ϫ Ϭ Ϫ ϫ caspase inhibitors could not rescue T cells from death. In addition ple value medium control) (high control medium control) 100, where the sample value is the average of absorbance values of the tripli- we show that ARD-induced T cell DNA damage appeared to re- cates of drug-treated cell supernatants after subtraction from each of the quire different caspase activities. The selective toxicity toward T absorbance values obtained in the background control.
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