A novel artemisinin derivative, 3-(12-beta-artemisininoxy) phenoxyl succinic acid (SM735), mediates immunosuppressive effects in vitro and in vivo.
OBJECTIVE
To study the immunosuppressive activity of SM735 {[3-(12-beta-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 IC(50) values of 0.33 micromol/L, 0.27 micromol/L, and 0.51 micromol/L, respectively. When compared with a CC(50) value of 53.1 micromol/L, SM735 had a favorable safety range. SM735 dose-dependently inhibited proinflammatory cytokine production [including interleukins (IL)-12, interferon (IFN)-gamma and IL-6] induced by LPS or PMA plus ionomycin. Upon ConA stimulation, SM735 suppressed IFN-gamma 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.


CONCLUSIONS
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 on SM735.
Zhou
Wen-liang
WL
Laboratories of Immunopharmacology and Synthetic Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, China.
Wu
Jin-ming
JM
Wu
Qing-li
QL
Wang
Jun-xia
JX
Zhou
Yu
Y
Zhou
Ru
R
He
Pei-lan
PL
Li
Xiao-yu
XY
Yang
Yi-fu
YF
Zhang
Yu
Y
Li
Ying
Y
Zuo
Jian-ping
JP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006461:Hemolysis / Q000187:drug effects; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013386:Succinates / Q000008:administration & dosage / Q000494:pharmacology*
C519322:3-(12-beta-artemisininoxy) phenoxyl succinic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D037621:Artemisinins; D016207:Cytokines; D007166:Immunosuppressive Agents; D013386:Succinates; D018664:Interleukin-12; D007371:Interferon-gamma