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 intr...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 99; no. 16; pp. 10617 - 10622
Main Authors Shim, Jae-Hyuck, Lee, Heung-Kyu, Chang, Eun-Ju, Chae, Wook-Jin, Han, Jin-Hwan, Han, Duck-Jong, Morio, Tomohiro, Yang, Jung-Jin, Bothwell, Alfred, Lee, Sang-Kyou
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 06.08.2002
National Acad Sciences
Subjects
Animals
Antifungal Agents - chemistry
Antifungal Agents - metabolism
Antifungal Agents - pharmacology
Apoptosis
B lymphocytes
Biological Sciences
Caspase 3
Caspase 9
Caspases - metabolism
Cell Division - drug effects
Cell lines
Cells
Cyclosporine - pharmacology
Furans
Heart Transplantation - immunology
HeLa Cells
Humans
Immunology
Immunosuppressants
Immunosuppressive Agents - chemistry
Immunosuppressive Agents - metabolism
Immunosuppressive Agents - pharmacology
Inductive reasoning
Jurkat Cells
Lipids
Lymphocyte Activation - drug effects
Molecular Structure
Molecules
Phosphorylation
Poly(ADP-ribose) Polymerases - metabolism
Proto-Oncogene Proteins c-bcl-2 - metabolism
Rats
Rats, Inbred Lew
Rats, Wistar
Receptor-CD3 Complex, Antigen, T-Cell - immunology
Signal Transduction - immunology
T lymphocytes
T-Lymphocytes - cytology
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
Transplantation
Transplants & implants
Tyrosine - metabolism
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Summary: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.
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This paper was submitted directly (Track II) to the PNAS office.
J.-H.S. and H.-K.L. contributed equally to this work.
To whom reprint requests should be addressed. E-mail: sjrlee@yonsei.ac.kr.
Edited by Charles A. Janeway, Jr., Yale University School of Medicine, New Haven, CT, and approved June 11, 2002
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.162522099