The new water-soluble artemisinin derivative SM905 ameliorates collagen-induced arthritis by suppression of inflammatory and Th17 responses.
OBJECTIVE
Our previous study showed that SM905, a novel artemisinin derivative, exhibited potent immunosuppressive activity. In this study, we evaluate preventive and therapeutic effect of SM905 on collagen-induced arthritis (CIA) in DBA/1 mice, and investigate its mechanisms both in inflammatory and autoimmune aspects of the disease.


METHODS
CIA was induced by type II bovine collagen (CII) in DBA/1 mice. SM905 was given orally either before (continuously 1 day before booster immunization) or after disease onset (continuously 14 days after booster immunization). Disease incidence and severity were monitored, mRNA expression of proinflammatory mediators was determined by real-time PCR, purified T cell proliferation was assessed using [(3)H]-thymidine incorporated assay, and T helper (Th) 17/Th1/Th2 type cytokine production was examined by ELISA.


RESULTS
Oral treatment with SM905 delayed disease onset, reduced arthritis incidence and severity, and suppressed the enhanced expression of pro-inflammatory cytokines, chemokines and chemokine receptors in draining lymph nodes. The CII-induced T cell proliferation and production of interleukin (IL)-17A by T cells were strikingly inhibited. Correspondingly, the mRNA expression of IL-17A and RORgamma t (a specific transcription factor for Th17) was also reduced. This effect was coupled with a striking reduction of IL-6 production, which has a critical role in Th17 development. In established arthritis, SM905 profoundly inhibited disease progression, reduced IL-17A and RORgamma t mRNA expression, and suppressed pro-inflammatory mediator expression in arthritic joints.


CONCLUSIONS
SM905 had beneficial effects on CIA by suppressing inflammatory and pathogenic Th17 responses.
Wang
J-X
JX
First Department of Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
Tang
W
W
Zhou
R
R
Wan
J
J
Shi
L-P
LP
Zhang
Y
Y
Yang
Y-F
YF
Li
Y
Y
Zuo
J-P
JP
D000818:Animals; D037621:Artemisinins / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000187:drug effects / Q000378:metabolism; D024043:Collagen Type II; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D020381:Interleukin-17 / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D019707:Receptors, Chemokine / Q000187:drug effects / Q000378:metabolism; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000378:metabolism
D037621:Artemisinins; D018925:Chemokines; D024043:Collagen Type II; D020381:Interleukin-17; D012333:RNA, Messenger; D019707:Receptors, Chemokine; C522065:SM905