Control of lupus by novel tryptophan metabolite 5-methoxytryptophan

[[abstract]]Bone marrow-derived mesenchymal stem cells (BMSCs) have great therapeutic potential for many diseases. However, stressful environment may lead BMSCs to premature senescence, resulting in altered cellular characteristics and functions. We had recently reported that high glucose (HG) stress induced BMSC senescence via up-regulating autophagy. Inhibition of ROS activity with N-acetylcysteine prevented BMSCs from HG-induced autophagy and senescence. In this study, we have determined the role of 5-methoxytryptophan (5-MTP) on preventing HG-induced BMSC senescence. 5-MTP was detected in the conditioned medium (CM) of BMSCs cultured at low glucose (LG) and reduced in CM of cells cultured at HG. Exogenous addition of 5-MTP reduced p21 and p16 expression in HG-induced senescent BMSCs. Moreover, 5-MTP attenuated the activity of senescence associated-β-galactocidase (SA-β-gal) in HG-BMSC. Since lysosomes have a crucial role on cellular senescence, we evaluated the effect of 5-MTP on lysosome by lysotracker staining. Lysotracker-positive cells were increased in HG-BMSCs compared to LG-BMSCs. 5-MTP addition abrogated lysosome increase in HG-BMSCs. Our data also revealed that 5-MTP reduced the glycosylation of LAMP-1, a membrane protein of lysosome which is involved in lysosome stabilization, in HG-BMSCs. Like the effects of 5-MTP, inhibition of LAMP-1 glycosylation with endoH in HG-BMSCs attenuated the lysosome mass and SA-β-gal activity. Furthermore, both 5-MTP and endoH could suppress the inflammatory cytokine, IL-6, secretion from HG-BMSCs. Taken together, these results indicate that 5-MTP prevents BMSCs from high glucose-induced senescence and secretory phenotype, which may be mediated by altering lysosome hemostasis