| Autor: |
Stefan Wirtz, Christoph Becker, Heiko Iven, Susanne Strand, Reza Mohammad Ahmadian, Daniela Poppe, Imke Tiede, Markus F. Neurath, Richard S. Blumberg, Peter R. Galle, Dennis Strand |
| Rok vydání: |
2003 |
| Předmět: |
|
| Zdroj: |
Gastroenterology. 124:A321 |
| ISSN: |
0016-5085 |
| Popis: |
Azathioprina and its metabolite 6-mercaptopurine (6-MP) are immuuosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohns disease. However, their molecular mechanism of action is un known. We found that azathioprine, 6-MP and 6-thioguanine induced apoptosis of T cells from patients with Crohns disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac 1 activation via b in drag of azathiopnne generated 6-ThioGTP to Racl instead of GTP. Binding of 6-Thio-GTP to Racl was associated with a strongly reduced exchange rate of hydrolyzed Thio-GDP suggesting that long-term treatment with azathioprine leads to accumulation of G DP-I oaded inactive Racl molecules in T cells. Interestingly, the activation of another GTPase, Ras, was not affected by azathioprine suggesting that the specificity of this drug for Rat1 is mediated by interaction of the sulfur group of 6-Thio-GTP with the GT Pase backbone. This prediction was supported by three dimensional modelling and analysis of van der Waal interaction energys between various GTPases and 6-ThioGTP. The activation of Racl target genes such as MEK, NF-kappaB and bd-xL was suppressed by aza thioprine leading to a mitochondnat pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Racl activity. This idea was supported by clinical data showing that azathioprine respons iveness in IBD pat ients is associated with a significant increase in the number of apoptotic T cells in the lamina propria, whereas non-responders showed no significant changes as compared to control patients. These findings explain the immunosuppressive effects o f azathioprine and suggest that 6-Thio-GTP denvates may be useful as potent novel immunosuppressive agents in autoimmune diseases and organ transplantation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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