Control of lupus by novel tryptophan metabolite 5-methoxytryptophan. (THER5P.907)

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of pathogenic autoantibodies which potentially drive immune-complex related inflammation in various tissues and organs. We previously identified that 5-methoxytryptophan (5-MTP), a soluble factor released by fibroblasts, provides endogenous control of proinflammatory cytokine-induced cyclooxgenase-2 expression. However, its effect on controlling systemic inflammation and systemic inflammatory disorders such as SLE remains unclear. Clinical studies by measuring serum 5-MTP concentrations found that a considerable amount of 5-MTP was detected in healthy subjects and was significantly reduced in SLE patients. Mouse models of experimental lupus-like disease induced by pristine shown that exogenous supplementation of 5-MTP not only prevented serum anti-dsDNA IgG production but also rescued the loss of body weight. Notably, 5-MTP administrations rescued kidney by reducing the accumulation of IgG. The beneficial effect of 5-MTP was correlated with inhibition of IL-6 production in bone-marrow derived dendritic cells treated with TLR7 ligand, which is a stimulator of lupus progression. Additionally, 5-MTP also suppressed Th1 cell while increased regulatory T cells which play an essential role in preventing autoimmunity. These results that 5-MTP is a novel circulating anti-inflammatory molecule which protects against excessive systemic inflammatory responses in animal models.