Abstract 13566: Pitavastatin Regulates mTOR Complex 1 Signaling Through Inhibition of Rheb in T Cells

Abstract

Accumulated evidence has shown that statins have anti-inflammatory and immunomodulatory effects; however, the mechanism has not been fully elucidated. Here we report that pitavastatin inhibited mTOR complex 1 (mTORC1) activity by inhibiting the farnesylation of the small GTPase Rheb in murine T cells. As a result of The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibition, statins regulate the biosynthesis of cholesterol and isoprenoid farnesylpyrophosphate (farnesyl-PP) that mediates the farnesylation and membrane association of Rheb. Pitavastatin-treated T cells failed to differentiate into T helper (Th)1 and Th17 cells, and this failure was rescued by adding farnesyl-PP. Pitavastatin and a farnesyltransferase inhibitor affected the transcription of T-bet and RORγT which have critical roles in the development of Th1 and Th17 cells respectively. In a mouse model of experimental autoimmune myocarditis, a CD4+ T cell-mediated disease, pitavastatin treatment ameliorated the pathophysiological severity of myocarditis associated with reduced Th1 and Th17 responses and mTORC1 signaling. We conclude that statins reduce the inflammatory functions and pathogenic activity of T cells through inhibition of mTORC1 signaling, and that this pathway may be a potential therapeutic target for Th1- and Th17-related diseases.