Fibroblast-like synoviocyte migration is enhanced by IL-17-mediated overexpression of L-type amino acid transporter 1 (LAT1) via the mTOR/4E-BP1 pathway.

Abstract

In rheumatoid arthritis (RA), activated synovial fibroblasts have the ability to invade joint cartilage, actively contributing to joint destruction in RA. The mechanisms underlying this cell migration and invasion remain unclear. Our previous results and data from the GEO profile indicate that the L-type amino acid transporter gene, LAT1, is overexpressed in the synovium of RA. To identify its potential role in RA, fibroblast-like synoviocytes (FLS) from patients with RA were used to determine the effects of suppressing the LAT1 genes using RNA interference and the LAT inhibitor, BCH. We found that BCH exposure reduced the phosphorylation of mTOR and its downstream target 4EBP1, radiolabeled leucine uptake, and migration of RA FLS. LAT1 silencing by siRNA presented effects similar to BCH inhibition. Treatment of cells with IL-17 stimulated the expression of LAT1. In contrast, applying an inhibitor of mTOR pathway, temsirolimus, or silencing eIF4E neutralized the stimulation of IL-17 on LAT1. BCH and siLAT1 also resulted in lower IL-17-stimulated leucine uptake and cell migration. These results suggest that the migration of RA FLS is aggravated by IL-17-mediated overexpression of LAT1 via mTOR/4E-BP1 pathway. In conclusion, further investigation is warranted into LAT1 as a potential target for drug therapies aimed at attenuating migration of transformed-appearing fibroblasts and subsequently preventing further erosion of bone and cartilage.