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Blood, 15 September 2005, Vol. 106, No. 6, pp. 2042-2049. Prepublished online as a Blood First Edition Paper on June 7, 2005; DOI 10.1182/blood-2005-01-0186. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-01-0186v1 106/6/2042    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Freeman, L. Articles by Chakraverty, R. Search for Related Content PubMed PubMed Citation Articles by Freeman, L. Articles by Chakraverty, R. Related Collections Immunobiology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Expression of 11-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells Lisa Freeman, Martin Hewison, Susan V. Hughes, Katie N. Evans, Deborah Hardie, Terry K. Means, and Ronjon Chakraverty From the Department of Hematology, University of Birmingham, Birmingham, United Kingdom; the Department of Medical Sciences, University of Birmingham, Birmingham, United Kingdom; and the Massachusetts General Hospital/Harvard Medical School, Center for Immunology and Inflammatory Diseases, Charlestown, MA. Glucocorticoids (GCs) exert powerful anti-inflammatory effects that may relate in part to their ability to restrict the differentiation and function of dendritic cells (DCs). Although these inhibitory effects are dependent upon GCs binding to nuclear glucocorticoid receptors (GRs), fine-tuning of GR signaling is achieved by prereceptor interconversion of cortisol that binds GRs with high affinity and cortisone that does not. We show for the first time that human monocyte-derived DCs are able to generate cortisol as a consequence of up-regulated expression of the enzyme 11-hydroxysteroid dehydrogenase type 1 (11-HSD1). Immature DCs demonstrate selective enhancement of 11-HSD1 reductase activity, leading to increased conversion of inactive cortisone to active cortisol. Enhancement of GC bioavailability is maintained or increased upon terminal differentiation induced by signals associated with innate immune activation. In marked contrast, maturation induced by CD40 ligation leads to a sharp reduction in cortisol generation by DCs. The differentiation of DCs from monocyte precursors is inhibited at physiologic concentrations of inactive cortisone, an effect that requires activity of the 11-HSD1 enzyme. In conclusion, prereceptor regulation of endogenous GCs appears to be an important determinant of DC function and represents a potential target for therapeutic manipulation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CD40 brings the shuttle down Cees van Kooten and Andrea M. Woltman Blood 2005 106: 1895-1896. [Full Text] [PDF] This article has been cited by other articles: I. Mascanfroni, M. d. M. Montesinos, S. Susperreguy, L. Cervi, J. M. Ilarregui, V. D. Ramseyer, A. M. Masini-Repiso, H. M. Targovnik, G. A. Rabinovich, and C. G. Pellizas Control of dendritic cell maturation and function by triiodothyronine FASEB J, April 1, 2008; 22(4): 1032 - 1042. [Abstract] [Full Text] [PDF] K Vagnerova, M Kverka, P Klusonova, P Ergang, I Miksik, H Tlaskalova-Hogenova, and J Pacha Intestinal inflammation modulates expression of 11{beta}-hydroxysteroid dehydrogenase in murine gut. J. Endocrinol., November 1, 2006; 191(2): 497 - 503. [Abstract] [Full Text] [PDF] C. U Onyimba, N. Vijapurapu, S J. Curnow, P. Khosla, P. M Stewart, P. I Murray, E. A Walker, and S. Rauz Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye. J. Endocrinol., August 1, 2006; 190(2): 483 - 493. [Abstract] [Full Text] [PDF] S. Rutella, G. Bonanno, A. Procoli, A. Mariotti, D. G. de Ritis, A. Curti, S. Danese, G. Pessina, S. Pandolfi, F. Natoni, et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features Blood, July 1, 2006; 108(1): 218 - 227. [Abstract] [Full Text] [PDF]

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