Changes in gene expression in cyclosporine A treated gingival fibroblasts
Date
2005
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Publisher
University of Delaware
Abstract
Cyclosporine A (CsA) is a potent immunosuppressant drug, produced by the fungus Tolypocladium inflatum, used to prevent allograft rejection after organ transplantation. It is distributed under the name Sandimmune® and has increased the success rate of transplants to approximately 95% over a one year period. The immunosuppressant effect is due to the effect of CsA on the serine-threonine Ca2+-calmodulin protein phosphatase calcineurin. Calcineurin is responsible for activation of NF-AT (nuclear factor of activated T cell) which translocates to the nucleus of the T cell to activate interleukin-2 for T cell maturation and proliferation. CsA complexes with cyclophilin and binds to calcineurin to inhibit its phosphatase activity thereby preventing T cell proliferation. ☐ A common side effect of CsA is gingival overgrowth. The exact cause of gingival overgrowth remains unsolved and controversy remains over whether the overgrowth is a result of hypertrophic growth or hyperplastic growth. In this study, gingival fibroblasts were used to examine whether gene changes after treatment with CsA cause hypertrophic growth, hyperplastic growth, or a combination of both. Gene arrays representing pathway specific genes associated with each form of growth, as well as cellular stains to examine nuclear and cytoskeletal changes, were employed to address the problem. Five genes expressed by gingival fibroblasts were identified from the arrays and selected for validation. The results indicate that Collagen 1α1 mRNA expression decreases after six days of treatment with CsA, but that overall there were modest changes in gene expression in gingival fibroblasts treated with CsA over a six day period. It was concluded that gingival fibroblasts are not solely responsible for the overgrowth seen in patients treated with CsA. Overgrowth is more likely due to a combination of factors involving paracrine interactions with the epithelium, endothelium, and tooth microenvironment.