The azathioprine molecule is composed of two moieties: mercaptopurine and an imidazole derivative ( 14, 18).
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However, inhibition of purine nucleotide biosynthesis with suppression of DNA and RNA synthesis and downregulation of B and T cell function have been suggested as major therapeutic mechanisms ( 13– 17). Although azathioprine has been in clinical use for about four decades ( 12), its precise mechanisms of action are still unknown. For instance, azathioprine has been therapeutically used in kidney ( 1) and heart ( 2) transplantation and various autoimmune and chronic inflammatory diseases, such as multiple sclerosis ( 3), rheumatoid arthritis ( 4), systemic lupus erythematosus ( 5), primary biliary cirrhosis ( 6), and inflammatory bowel diseases (IBDs) ( 7– 11). IntroductionĪzathioprine and its metabolite 6-mercaptopurine (6-MP) are widely used as immunosuppressive and anti-inflammatory agents in organ transplantation and the treatment of chronic inflammatory diseases. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-κB, and bcl-x L was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis.
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Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP.
![stata mp 14 activation key stata mp 14 activation key](https://oit.williams.edu/files/2014/06/matlabhpcc.png)
We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. 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. However, their molecular mechanism of action is unknown. 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.