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537.full - 0022-537545$20.00 THE JOURNAL OF PHARMACOLOGY...

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Selective Inhibition of Inflammatory Gene Expression in Activated T Lymphocytes: A Mechanism of Immune Suppression by Thiopurines Carlton W. Thomas, Gennett M. Myhre, Renee Tschumper, Raghavakaimal Sreekumar, Diane Jelinek, David J. McKean, James J. Lipsky, William J. Sandborn, and Laurence J. Egan Division of Gastroenterology and Hepatology (C.W.T., W.J.S., L.J.E.); Department of Molecular Pharmacology and Experimental Therapeutics (G.M.M., J.J.L., L.J.E.); Department of Immunology (D.J., D.J.M.); and Genomics Research Center (R.S.), Mayo Clinic, Rochester, Minnesota Received July 22, 2004; accepted September 21, 2004 ABSTRACT Azathioprine and 6-mercaptopurine are antimetabolite thiopu- rine drugs that play important roles in the treatment of leukemia and in the management of conditions requiring immunosup- pression, such as inflammatory bowel disease. The biochemi- cal pharmacology of these drugs suggests that inhibition of purine nucleotide formation through the 6-thioguanine nucleo- tide metabolites is their key molecular mechanism. However, it is unclear how these metabolites suppress immunity. We hy- pothesized that azathioprine produces a selective inhibitory effect on activated but not quiescent T lymphocytes. We first established a model system of T lymphocyte culture with aza- thioprine that produced pharmacologically relevant concentrations of 6-thioguanine nucleotides. Using genome-wide expression profiling, we identified a group of azathioprine-regulated genes in quiescent and activated T lymphocytes. Several genes involved in immunity and inflammation were selectively down-regulated by azathioprine in stimulated but not quiescent cells. Quantitative reverse transcription- polymerase chain reaction for three of these genes, tumor necrosis factor-related apoptosis-inducing ligand, tumor necrosis factor re- ceptor superfamily member 7, and 4-integrin, confirmed down- regulated expression of transcript levels. Tumor necrosis factor-re- lated apoptosis-inducing ligand protein expression was further studied and found to be inhibited by azathioprine, 6-mercaptopurine, and 6-thioguanine, implying that the inhibitory effects of azathioprine on expression are mediated by 6-thioguanine nucleotides. These results therefore provide a previously unrecognized molecular mech- anism for the immunosuppressive properties of thiopurine antime- tabolite drugs. The antimetabolite thiopurine medications azathioprine [AZA; 6-(1-methyl-4-nitroimidazol-5-yl)thiopurine] and 6-mer- captopurine (6-MP) are important therapies for both induction and maintenance of remission in patients with Crohn’s disease and ulcerative colitis (Pearson et al., 1995; Egan and Sandborn, 2004). Although originally developed for use in leukemia, AZA and 6-MP are now commonly used for their immunosuppressive properties in solid organ transplantation, autoimmune hepati- tis, rheumatoid arthritis, and autoimmune dermatological diseases in addition to inflammatory bowel disease (Lake et al., 2000). Once ingested, these drugs enter a metabolic path-
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