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INFLAMMATION AND IMMUNOPHARMACOLOGY

Selective Inhibition of Inflammatory Gene Expression in Activated T Lymphocytes: A Mechanism of Immune Suppression by Thiopurines

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

Azathioprine and 6-mercaptopurine are antimetabolite thiopurine drugs that play important roles in the treatment of leukemia and in the management of conditions requiring immunosuppression, such as inflammatory bowel disease. The biochemical pharmacology of these drugs suggests that inhibition of purine nucleotide formation through the 6-thioguanine nucleotide metabolites is their key molecular mechanism. However, it is unclear how these metabolites suppress immunity. We hypothesized 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 azathioprine 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 receptor superfamily member 7, and 4-integrin, confirmed down-regulated expression of transcript levels. Tumor necrosis factor-related 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 mechanism for the immunosuppressive properties of thiopurine antimetabolite drugs.

Address correspondence to: Dr. Laurence J. Egan, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905. E-mail: egan.laurence{at}mayo.edu

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