methyl-4-(adenin-9-yl)-2-hydroxybutanoate and Autoimmune-Diseases

Transmethylation affects several cellular events, including T cell activation, and blockade of this pathway may curtail inflammatory/autoimmune responses. Here, we demonstrate that transmethylation inhibition by a novel reversible S-adenosyl-l-homocysteine hydrolase inhibitor leads to immunosuppression by reducing phosphorylation of several key proteins involved in TCR signaling, including Akt, Erk1/2, and NF-kappaB. Remarkably, this effect was largely restricted to CD4 T cells and correlated with reduced arginine methylation of Vav1, an essential guanine nucleotide exchange factor in T cell stimulation. Treatment with the transmethylation inhibitor averted, and even ameliorated, the CD4-mediated autoimmune disease, experimental autoimmune encephalomyelitis. The data suggest that transmethylation is required for CD4 T cell activation, and its inhibition may be a novel approach in the treatment of multiple sclerosis, and other CD4-mediated autoimmune diseases.

Topics: Adenine; Adenosylhomocysteinase; Animals; Autoimmune Diseases; Butyrates; Calcium; CD4-Positive T-Lymphocytes; Down-Regulation; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Humans; Jurkat Cells; Lymphocyte Activation; Methylation; Mice; Proto-Oncogene Proteins c-vav; Receptors, Antigen, T-Cell; Signal Transduction