title: Thymus-derived glucocorticoids mediate androgen effects on thymocyte homeostasis.
abstract: Androgens contribute to the involution process of the aging thymus gland. However, molecular mechanisms behind this effect remain largely unknown. We have investigated the influence of testosterone on the ectopic synthesis of glucocorticoids (GCs) in thymocytes, an activity recently shown by us to be important for the homeostatic regulation of these cells. Castration, which leads to a strong increase in thymus tissue and function, was associated with a reduced GC release from thymocytes caused by down-regulated expression of several enzymes involved in GC synthesis, without affecting GC synthesis in the adrenals. Testosterone treatment of castrated male mice reversed these effects, also without affecting adrenal GC synthesis. The effects of testosterone in castrated mice on thymocyte homeostasis and GC release were strongly reduced in mice pretreated with the CYP11B1 enzyme inhibitor metyrapone, acting on the last step in the corticosterone synthesis. The androgen-induced thymic involution was dependent on GC action, because this was completely absent in mice lacking GC receptor (GR) expression specifically in thymocytes. We provide here an unrecognized mechanism how androgens contribute to thymic involution by stimulating local synthesis and release of GCs in the thymus.
authors.affiliation: Department of Bioscience and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Stockholm, Sweden. yongwen.chen@ki.se
authors.forename: Yongwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Shengjun
authors.initials: S
authors.lastname: Qiao
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.forename: Sam
authors.initials: S
authors.lastname: Okret
authors.forename: Mikael
authors.initials: M
authors.lastname: Jondal
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002369:Castration; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D016133:Polymerase Chain Reaction; D013739:Testosterone / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000728:Androgens; D005938:Glucocorticoids; D013739:Testosterone; D008797:Metyrapone
references.citation: Endocrinology. 1998 Feb;139(2):748-52
references.pmid: 9449649
references.citation: Endocr Rev. 2004 Dec;25(6):947-70
references.pmid: 15583024
references.citation: Trends Immunol. 2010 May;31(5):191-8
references.pmid: 20356793
references.citation: J Steroid Biochem Mol Biol. 1993 May;45(5):327-32
references.pmid: 8499342
references.citation: J Exp Med. 1994 Jun 1;179(6):1835-46
references.pmid: 8195711
references.citation: J Exp Med. 2008 Mar 17;205(3):711-23
references.pmid: 18332179
references.citation: Nat Immunol. 2004 Feb;5(2):133-9
references.pmid: 14749784
references.citation: Int Immunol. 2002 Jul;14(7):813-22
references.pmid: 12096041
references.citation: Int Immunopharmacol. 2001 Feb;1(2):321-8
references.pmid: 11360932
references.citation: Endocrinology. 2001 Mar;142(3):1278-83
references.pmid: 11181545
references.citation: Eur J Immunol. 2000 Sep;30(9):2586-92
references.pmid: 11009092
references.citation: Trends Immunol. 2009 Jul;30(7):366-73
references.pmid: 19540807
references.citation: J Clin Invest. 2007 May;117(5):1381-90
references.pmid: 17446934
references.citation: Neuroimmunomodulation. 2008;15(4-6):351-64
references.pmid: 19047811
references.citation: J Immunol. 1998 Jan 1;160(1):120-33
references.pmid: 9551964
references.citation: Trends Immunol. 2004 Nov;25(11):595-600
references.pmid: 15489188
references.citation: Eur J Immunol. 2001 Aug;31(8):2293-301
references.pmid: 11477541
references.citation: FASEB J. 2010 May;24(5):1340-6
references.pmid: 20056718
references.citation: Nat Rev Immunol. 2004 Nov;4(11):856-67
references.pmid: 15516965
references.citation: PLoS One. 2009 May 22;4(5):e5668
references.pmid: 19479077
references.citation: Mol Immunol. 2002 Mar;38(11):841-8
references.pmid: 11922942
references.citation: Gen Comp Endocrinol. 2008 Jul;157(3):266-74
references.pmid: 18486132
references.citation: Clin Exp Immunol. 2001 Sep;125(3):409-13
references.pmid: 11531948
references.citation: J Immunol. 2000 Feb 15;164(4):2180-7
references.pmid: 10657672
references.citation: Annu Rev Immunol. 2008;26:355-88
references.pmid: 18304000
references.citation: Nat Rev Immunol. 2009 Jan;9(1):57-62
references.pmid: 19104499
references.citation: J Endocrinol. 1993 Mar;136(3):389-97
references.pmid: 8473828
references.citation: Exp Cell Res. 2008 Oct 1;314(16):3027-35
references.pmid: 18638475
references.citation: Endocrinology. 2009 Sep;150(9):4163-9
references.pmid: 19406942
references.citation: Semin Immunol. 2007 Oct;19(5):318-30
references.pmid: 18023361
references.citation: J Clin Invest. 2009 Oct;119(10):3070-8
references.pmid: 19770514
references.citation: J Immunol. 2005 Aug 15;175(4):2741-53
references.pmid: 16081852
references.citation: J Steroid Biochem Mol Biol. 2010 May 31;120(2-3):69-75
references.pmid: 20346397
references.citation: Neuroimmunomodulation. 2008;15(4-6):290-322
references.pmid: 19047807
references.citation: J Immunol. 1989 Oct 1;143(7):2185-92
references.pmid: 2550550
references.citation: Endocrinology. 2005 Jun;146(6):2501-7
references.pmid: 15731366
references.citation: Endocr Rev. 2009 Dec;30(7):883-925
references.pmid: 19887492