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      Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response

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          Abstract

          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.

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          Most cited references35

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          Transforming growth factor beta in tissue fibrosis.

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            STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.

            Interleukin-17 (IL-17)-producing helper T (TH) cells, named as TH(IL-17), TH17, or inflammatory TH (THi), have been recently identified as a novel effector lineage. However, how cytokine signals mediate THi differentiation is unclear. We found that IL-6 functioned to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor gamma-T (RORgamma t), a THi-specific transcriptional regulator; STAT3 deficiency impaired RORgamma t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression.
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              Dendritic cell regulation of TH1-TH2 development.

              Understanding the control exerted by cytokines on T helper cell subsets 1 and 2 (TH1-TH2) development has progressed to a fairly satisfying knowledge of intracellular signals and transcription factors. Less is understood about the molecular basis of TH1-TH2 development exerted by other parameters, such as how the antigen presenting cell can influence this process. Recent work suggests that dendritic cell subsets contribute significant polarizing influences on T helper differentiation, but how this comes about is less clear. In some cases known pathways may be used, as in the dendritic cell subset 1 exerting TH1 polarization by interleukin 12 (IL-12) production and STAT4 activation. In others, the effects are still in need of explanation.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                February 2014
                30 December 2013
                : 35
                : 2
                : 219-229
                Affiliations
                [1 ]Laboratory of Immunopharmacology, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China
                [2 ]Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine , Shanghai 201203, China
                Author notes
                [#]

                These authors contributed equally to this work.

                Article
                aps2013167
                10.1038/aps.2013.167
                4651227
                24374810
                af3f33db-6f8d-43b8-8cc1-899d2441f37a
                Copyright © 2014 CPS and SIMM
                History
                : 11 September 2013
                : 02 October 2013
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                sahh inhibitor,toll-like receptor signaling,antigen-presenting cell,systemic lupus erythematosus

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