Inhibition of the CD8+ T cell-mediated cytotoxicity reaction by hypericin: potential for treatment of T cell-mediated diseases.
The cytotoxicity reaction of murine CD8 T lymphocytes has been found to be strongly inhibited by nanomolar concentrations of hypericin, a lipophilic dianthraquinone with photodynamic properties. Cytotoxic T lymphocyte (CTL)-induced target cell apoptosis, as well as exocytosis of cytolytic granules from these cells, were ablated by hypericin, administered at the onset of the reaction, without affecting CTL viability. The inhibition of cytolysis occurred without the light irradiation which is essential for photosensitization. The findings suggest that the action of hypericin targets the effector CTL; however, apoptosis induced in murine L-cells with recombinant tumor necrosis factor (TNF)-alpha was also prevented by hypericin. Since hypericin is a known inhibitor of protein kinase C, MAP kinase and at least one other tyrosine kinase, this inhibitory activity could play a role in the down-modulation of CTL-induced cytotoxicity. Furthermore, our studies show that the action of hypericin induces rapid dephosphorylation of phospholipids associated with low-density membranes in CTL, but not with membranes of the cytotoxic granules. The ability of hypericin to interfere with cytotoxicity may render it useful in the treatment of T cell-mediated diseases.
Lavie
G
G
Institute of Hematology and Blood Transfusion Center, Sheba Medical Center, Tel-Hashomer 52621, Israel.
Meruelo
D
D
Aroyo
K
K
Mandel
M
M
D000818:Animals; D000873:Anthracenes; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005089:Exocytosis / Q000187:drug effects / Q000276:immunology; D007154:Immune System Diseases / Q000188:drug therapy* / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D008027:Light; D051379:Mice; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
D000873:Anthracenes; D007166:Immunosuppressive Agents; D008024:Ligands; D010743:Phospholipids; D018124:Receptors, Tumor Necrosis Factor; D010569:Perylene; C004965:hypericin