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Rosmarinic Acid Induces p56^lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction ¹

Yun-Gyoung Hur^*, Yungdae Yun and Jonghwa Won^2,*

^* Mogam Biotechnology Research Institute, Yongin City, Gyunggido, Korea; and Division of Molecular Life Science and Center for Cell Signaling Research, Ewha Women’s University, Seoul, Korea

Apoptosis is one way of controlling immune responses, and a variety of immunosuppressive drugs suppress harmful immune responses by inducing apoptosis of lymphocytes. In this study we observed that rosmarinic acid, a secondary metabolite of herbal plants, induced apoptosis in an p56^lck (Lck)-dependent manner; Lck⁺ Jurkat T cells undergo apoptosis in response to rosmarinic acid (RosA) treatment, whereas Lck^- Jurkat subclone J.CaM1.6 cells do not. J.CaM1.6 cells with various Lck mutants indicated that Lck SH2 domain, but not Lck kinase activity, was required for RosA-induced apoptosis. RosA induced apoptosis in the absence of a TCR stimulus, and this was not prevented by interruption of the Fas/Fas ligand interaction. Instead, RosA-mediated apoptosis involved a mitochondrial pathway as indicated by cytochrome c release and the complete blockage of apoptosis by an inhibitor of mitochondrial membrane depolarization. Both caspase-3 and -8 were indispensable in RosA-induced apoptosis and work downstream of mitochondria and caspase-9 in the order of caspase-9/caspase-3/caspase-8. In freshly isolated human PBMC, RosA specifically induced apoptosis of Lck⁺ subsets such as T and NK cells, but not Lck-deficient cells, including B cells and monocytes. Moreover, RosA’s ability to kill T and NK cells was restricted to actively proliferating cells, but not to resting cells. In conclusion, Lck-dependent apoptotic activity may make RosA an attractive therapeutic tool for the treatment of diseases in which T cell apoptosis is beneficial.

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