Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response
Abstract
Shi-jun HE1, #, Ze-min LIN2, #, Yan-wei WU1, Bing-xin BAI2, Xiao-qian YANG1, Pei-lan HE1, Feng-hua ZHU1, Wei TANG1, *, Jian-ping ZUO1, 2, *
1Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Aim: To examine the therapeutic effects and underlying mechanisms of DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, on lupus-prone female NZB×NZW F1 (NZB/W F1) mice.
Methods: Female NZB/W F1 mice were treated orally with DZ2002 (0.5 mg·kg-1·d-1) for 11 weeks, and the proteinuria level and body weight were monitored. After the mice ware euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of NZB/W F1 mice were isolated for ex vivo study. Toll-like receptor (TLR)-stimulated human peripheral blood mononuclear cells (PBMCs) or murine bone marrow-derived dendritic cells (BMDCs) were used for in vitro study.
Results: Treatment of the mice with DZ2002 significantly attenuated the progression of glomerulonephritis and improved the overall health. The improvement was accompanied by decreased levels of nephritogenic anti-dsDNA IgG2a and IgG3 antibodies, serum IL-17, IL-23p19 and TGF-β. In ex vivo studies, treatment of the mice with DZ2002 suppressed the development of pathogenic Th17 cells, significantly decreased IL-17, TGF-β, IL-6, and IL-23p19 production and impeded activation of the STAT3 protein and JNK/NF-κB signaling in splenocytes. DZ2002 (500 μmol/L) significantly suppressed TLR agonists-stimulated up-regulation in IL-6, IL-12p40, TNF-α, and IgG and IgM secretion as well as in HLA-DR and CD40 expression of dendritic cells among human PBMCs in vitro. DZ2002 (100 μmol/L) also significantly suppressed TLR agonists-stimulated up-regulation in IL-6 and IL-23p19 production in murine BMDCs, and prevented Th17 differentiation and suppressed IL-17 secretion by the T cells in a BMDC-T cell co-culture system.
Conclusion: DZ2002 effectively ameliorates lupus syndrome in NZB/W F1 mice by regulating TLR signaling-mediated antigen presenting cell (APC) responses.
Keywords: SAHH inhibitor; Toll-like receptor signaling; antigen-presenting cell; systemic lupus erythematosus
This work was supported by grants from the National Natural Science Foundation of China (NSFC) (No 81072652, 81273524, and 81273525); the National Science & Technology Major Project “New Drug Creation and Manufacturing Program”, China (2012ZX09102-101-006); and the Science & Technology Commission of Shanghai Municipality, China (11431921102).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail jpzuo@mail.shcnc.ac.cn (Jian-ping ZUO); tangwei@mail.shcnc.ac.cn (Wei TANG)
Received 2013-09-11 Accepted 2013-10-02
Keywords:
1Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Aim: To examine the therapeutic effects and underlying mechanisms of DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, on lupus-prone female NZB×NZW F1 (NZB/W F1) mice.
Methods: Female NZB/W F1 mice were treated orally with DZ2002 (0.5 mg·kg-1·d-1) for 11 weeks, and the proteinuria level and body weight were monitored. After the mice ware euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of NZB/W F1 mice were isolated for ex vivo study. Toll-like receptor (TLR)-stimulated human peripheral blood mononuclear cells (PBMCs) or murine bone marrow-derived dendritic cells (BMDCs) were used for in vitro study.
Results: Treatment of the mice with DZ2002 significantly attenuated the progression of glomerulonephritis and improved the overall health. The improvement was accompanied by decreased levels of nephritogenic anti-dsDNA IgG2a and IgG3 antibodies, serum IL-17, IL-23p19 and TGF-β. In ex vivo studies, treatment of the mice with DZ2002 suppressed the development of pathogenic Th17 cells, significantly decreased IL-17, TGF-β, IL-6, and IL-23p19 production and impeded activation of the STAT3 protein and JNK/NF-κB signaling in splenocytes. DZ2002 (500 μmol/L) significantly suppressed TLR agonists-stimulated up-regulation in IL-6, IL-12p40, TNF-α, and IgG and IgM secretion as well as in HLA-DR and CD40 expression of dendritic cells among human PBMCs in vitro. DZ2002 (100 μmol/L) also significantly suppressed TLR agonists-stimulated up-regulation in IL-6 and IL-23p19 production in murine BMDCs, and prevented Th17 differentiation and suppressed IL-17 secretion by the T cells in a BMDC-T cell co-culture system.
Conclusion: DZ2002 effectively ameliorates lupus syndrome in NZB/W F1 mice by regulating TLR signaling-mediated antigen presenting cell (APC) responses.
Keywords: SAHH inhibitor; Toll-like receptor signaling; antigen-presenting cell; systemic lupus erythematosus
This work was supported by grants from the National Natural Science Foundation of China (NSFC) (No 81072652, 81273524, and 81273525); the National Science & Technology Major Project “New Drug Creation and Manufacturing Program”, China (2012ZX09102-101-006); and the Science & Technology Commission of Shanghai Municipality, China (11431921102).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail jpzuo@mail.shcnc.ac.cn (Jian-ping ZUO); tangwei@mail.shcnc.ac.cn (Wei TANG)
Received 2013-09-11 Accepted 2013-10-02