Immunosuppressive effects of tautomycetin in vivo and in vitro via T cell-specific apoptosis induction.
Tautomycetin (TMC) was identified as an immunosuppressor of activated T cells. Inhibition of T cell proliferation with TMC was observed at concentrations 100-fold lower than those needed to achieve maximal inhibition with cyclosporin A (CsA). TMC specifically blocked tyrosine phosphorylation of intracellular signal mediators downstream of Src tyrosine kinases in a T cell-specific manner, leading to apoptosis due to cleavage of Bcl-2, caspase-9, caspase-3, and poly(ADP-ribose) polymerase, but not caspase-1. In TMC-treated rats that received a heterotopic cardiac allograft, the graft survived more than 160 days, comparable to graft survival in allografted rats treated with CsA. Thus, TMC, whose mechanism of action is different from that of CsA or FK506, can be used as a potent T cell-specific immunosuppressor.
Shim
Jae-Hyuck
JH
Department of Biotechnology, College of Engineering and Bioproducts Research Center, Yonsei University, Seoul, Korea.
Lee
Heung-Kyu
HK
Chang
Eun-Ju
EJ
Chae
Wook-Jin
WJ
Han
Jin-Hwan
JH
Han
Duck-Jong
DJ
Morio
Tomohiro
T
Yang
Jung-Jin
JJ
Bothwell
Alfred
A
Lee
Sang-Kyou
SK
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D005663:Furans; D006367:HeLa Cells; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019169:Jurkat Cells; D008055:Lipids; D008213:Lymphocyte Activation / Q000187:drug effects; D015394:Molecular Structure; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism
D000935:Antifungal Agents; D005663:Furans; D007166:Immunosuppressive Agents; D008055:Lipids; D019253:Proto-Oncogene Proteins c-bcl-2; D017260:Receptor-CD3 Complex, Antigen, T-Cell; C058744:tautomycetin; D014443:Tyrosine; D016572:Cyclosporine; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases