Abstract
Aim:
To study the immunosuppressive activity of SM735 {[3 -(12-β-artemisininoxy)] phenoxyl succinic acid}, a synthetic artemisinin derivative with nonsteroidal anti-inflammatory drug structure, with the aim of finding potential immunosuppressive agents.
Methods:
Concanavalin A (ConA), lipopolysaccharide (LPS), and mixed lymphocyte reaction (MLR), were used to induce the proliferation of splenocytes, and [3H]-thymidine incorporation was used to evaluate the proliferation of splenocytes. Cytokine production was promoted with ConA, LPS, or PMA plus ionomycin, and was detected with the enzyme-linked immunosorbent assay. Dinitrofluorobenzene (DNFB) and sheep red blood cells (SRBC) were used to induce delayed-type hypersensitivity and quantitative hemolysis of SRBC (QHS) mouse models, as criteria for the evaluation of in vivo immune activity.
Results:
SM735 strongly inhibited the proliferation of splenocytes induced by ConA, LPS, or MLR, with IC50 values of 0.33 μmol/L, 0.27 μmol/L, and 0.51 μmol/L, respectively. When compared with a CC50 value of 53.1 μmol/L, SM735 had a favorable safety range. SM735 dose-dependently inhibited proinflammatory cytokine production [including interleukins (IL)-12, interferon (IFN)-γ and IL-6] induced by LPS or PMA plus ionomycin. Upon ConA stimulation, SM735 suppressed IFN-γ in a dose-dependent manner, but did not affect IL-2 secretion. SM735 also strongly suppressed both T-cell-mediated delayed-type hypersensitivity (DTH) and B-cell-mediated QHS reactions.
Conclusion:
SM735 had strong immunosuppressive activity in vitro and in vivo, suggesting a potential role for SM735 as an immunosuppressive agent, and established the groundwork for further research onSM735.
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References
Luo XD, Shen CC . The chemistry, pharmacology, and clinical applications of qinghaosu (artemisinin) and its derivatives. Med Res Rev 1987; 7: 29–52.
Klayman DL . Qinghaosu (artemisinin): an antimalarial drug from China. Science 1985; 228: 1049–55.
Li Y, Wu YL . An over four millennium story behind qinghaosu (artemisinin): a fantastic antimalarial drug from a traditional Chinese herb. Curr Med Chem 2003; 10: 2197–230.
Tawfik AF, Bishop, SJ, Ayalp A, el-Feraly FS . Effects of artemisinin, dihydroartemisinin and arteether on immune responses of normal mice. Int J Immunopharmacol 1990; 12: 385–9.
Yu Q, ** H . Artesunate in treatment of dermatosis. Bengbu Yixueyuan Xuebao 1997; 22: 309–10 Chinese.
Yu Q, Gao Y . Systemic lupus erythematosus treated with artesunate. Chin J Dermatol 1997; 30: 51–2 Chinese.
Zhang J, Zhong J, Shi Z, Dai X . Effects of lingdan and artesunate on T cell populations in human SLE. Chin Interg Tradit West Med 2002; 7: 489 Chinese.
Meshnick SR, Taylor TE, Kamchonwongpaisan S . Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 1996; 60: 301–15.
Yang YZ, Little B, Meshnick SR . Alkylation of proteins by artemisinin. Effects of heme, pH, and drug structure. Biochem Pharmacol 1994; 48: 569–73.
Yang ZS, Zhou WL, Sui Y, Wang JX, Wu JM, Zhou Y, et al. Synthesis and immunosuppressive activity of new artemisinin derivatives. Part I. [12(β or α)-dihydroartemisininoxy] phen(ox)yl aliphatic acids/esters. J Med Chem 2005; 48: 4608–17.
Allison AC . Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology 2000; 47: 63–83.
Liu J . FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol Today 1993; 14: 290–5.
Noori S, Naderi GA, Hassan ZM, Bathaie SZ, Hashemi SM . Immunosuppressive activity of a molecule isolated from Artemisia annua on DTH responses compared with cyclosporin A. Int Immunopharmacol 2004; 4: 1301–6.
Rowland TL, McHugh SM, Deighton J, Dearman RJ, Ewan PW, Kimber I . Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mono-nuclear cells. Immunopharmacology 1998; 40: 11–20.
Feng YH, Zhou WL, Wu QL, Li XY, Zhao WM, Zou JP . Low dose of resveratrol enhanced immune response of mice. Acta Pharmacol Sin 2002; 23: 893–7.
Wu QL, Fu YF, Zhou WL, Wang TX, Feng YH, Liu, J, et al. Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression. J Pharmacol Exp Ther 2005; 313: 705–11.
Phanuphak P, Moorhead JW, Claman HN . Tolerance and contact sensitivity to DNFB in mice. I. In vivo detection by ear swelling and correlation with in vitro cell stimulation. J Immunol 1974; 112: 115–23.
Simpson MA, Gozzo JJ . Spectrophotometric determination of lymphocyte mediated sheep red blood cell hemolysis in vitro. J Immunol Methods 1978; 21: 159–65.
Bin-Hafeez B, Ahmad I, Haque R, Raisuddin S . Protective effect of Cassia occidentalis L on cyclophosphamide-induced suppression of humoral immunity in mice. J Ethnopharmacol 2001; 75: 13–8.
Toungouz M, Donckier V, Goldman M . Tolerance induction in clinical transplantation: the pending questions. Transplantation 2003; 75 Suppl 9: 58S–60S.
Offermann G . Immunosuppression for long-term maintenance of renal allograft function. Drugs 2004; 64: 1325–38.
Tourkova IL, Yurkovetsky ZR, Shurin MR, Shurin GV . Mechanisms of dendritic cell-induced T cell proliferation in the primary MLR assay. Immunol Lett 2001; 78: 75–82.
Amrolia PJ, Muccioli-Casadei G, Yvon E, Huls H, Sili U, Wieder ED, et al. Selective depletion of donor allo-reactive T-cells without loss of anti-viral or anti-leukemic responses. Blood 2003; 102: 2292–9.
Tiercy JM, Villard J, Roosnek E . Selection of unrelated bone marrow donors by serology, molecular ty** and cellular assays. Transpl Immunol 2002; 10: 215–21.
Goes N, Chandraker A . Human leukocyte antigen matching in renal transplantation: an update. Curr Opin Nephrol Hypertens 2000; 9: 683–7.
Firestein GS . The T cell cometh: interplay between adaptive immunity and cytokine networks in rheumatoid arthritis. J Clin Invest 2004; 114: 471–4.
Matei I, Matei L . Cytokine patterns and pathogenicity in autoimmune diseases. Rom J Intern Med 2002; 40: 27–41.
Semenkov VF, Artemjeva OV, Shishina RN, Golubeva VL, Serova LD . Influence of clinical immunosuppression on proinflammatory cytokines and acute-phase proteins. Transplant Proc 1998; 30: 4195.
Malek TR, Bayer AL . Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004; 4: 665–74.
Frew AJ, Varney VA, Gaga M, Kay AB . Immunohistology of human allergic late-phase skin reactions. Skin Pharmacol 1991; 4 Suppl 1: 71–8.
Yamachika E, Habte T, Oda D . Artemisinin: an alternative treatment for oral squamous cell carcinoma. Anticancer Res 2004; 24: 2153–60.
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Project supported by the Knowledge Innovation Program of the Chinese Academy of Sciences (No KSCX2-SW-202).
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Zhou, Wl., Wu, Jm., Wu, Ql. et al. A novel artemisinin derivative, 3-(12-β-artemisininoxy) phenoxyl succinic acid (SM735), mediates immunosuppressive effects in vitro and in vivo. Acta Pharmacol Sin 26, 1352–1358 (2005). https://doi.org/10.1111/j.1745-7254.2005.00232.x
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DOI: https://doi.org/10.1111/j.1745-7254.2005.00232.x
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