Rosmarinic acid induces p56lck-dependent apoptosis in Jurkat and peripheral T cells via mitochondrial pathway independent from Fas/Fas ligand interaction.
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.
Hur
Yun-Gyoung
YG
Mogam Biotechnology Research Institute, 304 Bojungri, Goosungeup, Yongin City, Gyunggido 449-913, Korea.
Yun
Yungdae
Y
Won
Jonghwa
J
D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D017252:CD3 Complex / Q000502:physiology; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology*; D053630:Depsides; D053222:Fas Ligand Protein; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D014162:Transfection; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*; D018909:src Homology Domains / Q000187:drug effects / Q000276:immunology; D000097123:Rosmarinic Acid
D017252:CD3 Complex; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D002934:Cinnamates; D053630:Depsides; D053222:Fas Ligand Protein; D008024:Ligands; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008562:Membrane Glycoproteins; D019014:fas Receptor; D000097123:Rosmarinic Acid; C505661:FASLG protein, human; C505407:CASP3 protein, human; C505530:CASP8 protein, human