Background and aims S-Adenosyl-l-homocysteine hydrolase (SAHH) is a highly conserved ubiquitous enzyme that catalyses the hydrolysis of S-adenosyl-l-homocysteine (SAH) to adenosine (Ado) and homocysteine (Hcy) in eukaryotic cells. The reversible type III SAHH inhibitor DZ2002 has been found to have an immunomodulatory function and to alleviate disease in several inflammatory and autoimmune animal models, with greatly reduced cytotoxicity. This study was aim to examine the therapeutic effects and underlying mechanisms of DZ2002 on lupus-prone female NZB/W F1 mice.
Methods NZB/W F1 mice were treated orally with DZ2002 (0.5 mg kg-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 PBMCs or murine bone marrow-derived dendritic cells were used for in vitro study.
Results Our study demonstrated that DZ2002 exerted a therapeutic effect on NZB/W F1 mice with established nephritis. The mechanism involves the modulation of T cell development in lupus by interfering with TLR-triggered APC function. Further study explored the regulatory mechanisms of SAHH on DC function in both innate and adaptive immune system, using the SAHH inhibitor with definite target and potent immunosuppressive activity.
Conclusions The present issue demostrated that the reversible SAHH inhibitor DZ2002 effectively ameliorates lupus syndrome in NZB/W F1 mice by regulating TLR signaling-mediated APC responses. This compound is prospective to become a novel drug for SLE treatment with Hcy as a potential biomarker in autoimmune disease.
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