CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes
| Autor: | Imke Tiede, Kai Hildner, Radovan Dvorsky, Christoph Becker, Peter R. Galle, Heiko Iven, Stefan Wirtz, Brigitte Bartsch, Susanne Strand, Jonas Mudter, Markus F. Neurath, Daniela Poppe, Gerhard Fritz, Martin H. Holtmann, Mohammad Reza Ahmadian, Dennis Strand, Hans A. Lehr, Raja Atreya, Richard S. Blumberg, Henning Walczak |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Adult
CD4-Positive T-Lymphocytes STAT3 Transcription Factor rac1 GTP-Binding Protein medicine.medical_specialty Apoptosis RAC1 Azathioprine Protein Serine-Threonine Kinases Biology Lymphocyte Activation Organ transplantation Tioguanine CD28 Antigens medicine Humans Phosphorylation Protein kinase A Cells Cultured Aged Kinase CD28 General Medicine Middle Aged I-kappa B Kinase DNA-Binding Proteins Immunology Trans-Activators Commentary Cancer research Immunosuppressive Agents medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 111:1133-1145 |
| ISSN: | 0021-9738 |
| Popis: | Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific block- ade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-κB, and bcl-xL was suppressed by azathioprine, leading to a mito- chondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptot- ic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of aza- thioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation. |
| Databáze: | OpenAIRE |
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