(5R)-5-hydroxytriptolide attenuated collagen-induced arthritis in DBA/1 mice via suppressing interferon-gamma production and its related signaling.
(5R)-5-Hydroxytriptolide (LLDT-8) displays strong immunosuppressive activities both in vitro and in vivo in our previous studies. This study aims to investigate whether LLDT-8 has antiarthritic potential in a murine model of type II bovine collagen (CII)-induced arthritis (CIA) and to show the mechanism(s) of LLDT-8 action. DBA/1 mice were immunized with CII to induce arthritis and administered with LLDT-8. The severity of arthritis was evaluated according to the clinical score and joint damage. The effects of LLDT-8 on immune responses were determined by measurement of serum antibody levels, lymphocyte proliferation assay, cytokine assay, nitric oxide (NO) production, arginase activity assays, fluorescence-activated cell sorting analysis of splenic Mac-1+ cells, as well as polymerase chain reaction analysis for interferon-gamma (IFN-gamma)-related gene expression. We showed that LLDT-8 treatment significantly reduced the incidence and severity of CIA. The preventive and therapeutic effects of LLDT-8 are associated with 1) reduction of serum anti-CII immunoglobulin (Ig) G, IgG2a, and IgG1 levels; 2) inhibition of CII-specific lymphocyte proliferation, IFN-gamma and interleukin-2 production; 3) blockade of gene expressions in IFN-gamma signaling, including IFN-gamma production pathways [signal transducer and activator of transcription (STAT) 1, T-box transcription factor, interleukin 12Rbeta2, and STAT4] and IFN-gamma-induced chemokine transcription [macrophage inflammatory protein (Mip)-1alpha, Mip-1beta, regulated on activation normally T cell expressed and secreted, and inducible protein 10]; and 4) retardation of the abnormal increase of NO via IFN-gamma/STAT1/interferon regulatory factor 1/inducible nitric-oxide synthase pathway and arginase activity. Moreover, the mRNA transcription of chemokine receptors was also suppressed [including C-C chemokine receptor (CCR) 1, CCR5, and C-X-C chemokine receptor 3]. In conclusion, our data suggest that the antiarthritic effect of LLDT-8 is closely related to the blockade of IFN-gamma signaling. LLDT-8 may have a therapeutic value in the treatment of rheumatoid arthritis.
Zhou
Ru
R
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
Tang
Wei
W
Ren
Yong-Xin
YX
He
Pei-Lan
PL
Zhang
Fan
F
Shi
Li-Ping
LP
Fu
Yun-Feng
YF
Li
Yuan-Chao
YC
Ono
Shiro
S
Fujiwara
Hiromi
H
Yang
Yi-Fu
YF
Zuo
Jian-Ping
JP
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D008811:Mice, Inbred DBA; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
C509074:5-hydroxytriptolide; D004224:Diterpenes; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase