methyl-4-(adenin-9-yl)-2-hydroxybutanoate and Lupus-Erythematosus--Systemic

Post-translational protein modifications can play a significant role in immune cell signaling. Recently, we showed that inhibition of transmethylation curtails experimental autoimmune encephalomyelitis, notably by reducing T cell receptor (TCR)-induced activation of CD4(+) T cells. Here, we demonstrate that transmethylation inhibition by a reversible S-adenosyl-l-homocysteine hydrolase inhibitor (DZ2002) led to immunosuppression by reducing TLR-, B cell receptor (BCR)- and TCR-induced activation of immune cells, most likely by blocking NF-κB activity. Moreover, prophylactic treatment with DZ2002 prevented lupus-like disease from developing in both BXSB and MRL-Fas(lpr) mouse models. DZ2002 treatment initiated during active disease significantly improved outcomes in both in vivo models, suggesting methylation inhibition as a novel approach for the treatment of autoimmune/inflammatory diseases.

Topics: Adenine; Animals; Antigen-Presenting Cells; Autoantibodies; B-Lymphocytes; Butyrates; CD4-Positive T-Lymphocytes; Cytokines; Disease Models, Animal; Female; Immunoglobulin G; Immunosuppressive Agents; Kidney; Lupus Erythematosus, Systemic; Male; Methylation; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Protein Processing, Post-Translational; Signal Transduction; Toll-Like Receptors