Abstract
Glucocorticoids, acting through the glucocorticoid receptor, potently modulate immune function and are a mainstay of therapy for treatment of inflammatory conditions, autoimmune diseases, leukemias and lymphomas1. Moreover, removal of systemic glucocorticoids, by adrenalectomy in animal models or adrenal insufficiency in humans, has shown that endogenous glucocorticoid production is required for regulation of physiologic immune responses2. These effects have been attributed to suppression of cytokines, although the crucial cellular and molecular targets remain unknown3. In addition, considerable controversy remains as to whether glucocorticoids are required for thymocyte development4,5,6,7. To assess the role of the glucocorticoid receptor in immune system development and function, we generated T-cell-specific glucocorticoid receptor knockout mice. Here we show that the T-cell is a critical cellular target of glucocorticoid receptor signaling, as immune activation in these mice resulted in significant mortality. This lethal activation is rescued by cyclooxygenase-2 (COX-2) inhibition but not steroid administration or cytokine neutralization. These studies indicate that glucocorticoid receptor suppression of COX-2 is crucial for curtailing lethal immune activation, and suggest new therapeutic approaches for regulation of T-cell-mediated inflammatory diseases.
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Acknowledgements
We thank E. Unanue, R. Schreiber and J. Gitlin for critical review of this manuscript; A. Cheng for insightful discussions and critical review of this manuscript; E. Plut, M. Wallace and the Washington University Mouse Genetics Core for embryonic stem cell injections; K. Hamilton and the Siteman Cancer Center Genechip Facility for microarray experimentation; K. Sheehan and R. Schreiber for providing neutralizing antibodies to IFN-γ; and Pharmacia Corporation for providing SC-236. This work was supported by grants from the National Institutes of Health and the Pharmacia–Washington University Biomedical Research Program (L.J.M.) and the Medical Scientist Training Program (J.A.B.).
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L.J.M. and B.P.S. received research support from Pharmacia Corp. as part of the Washington University/Pharmacia Biomedical Research Program. H.F. is employed Pharmacia Corp. (now part of Pfizer Inc.)
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Brewer, J., Khor, B., Vogt, S. et al. T-cell glucocorticoid receptor is required to suppress COX-2-mediated lethal immune activation. Nat Med 9, 1318–1322 (2003). https://doi.org/10.1038/nm895
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DOI: https://doi.org/10.1038/nm895
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