Thymus-derived glucocorticoids mediate androgen effects on thymocyte homeostasis.
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.
Chen
Yongwen
Y
Department of Bioscience and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Stockholm, Sweden. yongwen.chen@ki.se
Qiao
Shengjun
S
Tuckermann
Jan
J
Okret
Sam
S
Jondal
Mikael
M
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
D000728:Androgens; D005938:Glucocorticoids; D013739:Testosterone; D008797:Metyrapone
Endocrinology. 1998 Feb;139(2):748-52
9449649
Endocr Rev. 2004 Dec;25(6):947-70
15583024
Trends Immunol. 2010 May;31(5):191-8
20356793
J Steroid Biochem Mol Biol. 1993 May;45(5):327-32
8499342
J Exp Med. 1994 Jun 1;179(6):1835-46
8195711
J Exp Med. 2008 Mar 17;205(3):711-23
18332179
Nat Immunol. 2004 Feb;5(2):133-9
14749784
Int Immunol. 2002 Jul;14(7):813-22
12096041
Int Immunopharmacol. 2001 Feb;1(2):321-8
11360932
Endocrinology. 2001 Mar;142(3):1278-83
11181545
Eur J Immunol. 2000 Sep;30(9):2586-92
11009092
Trends Immunol. 2009 Jul;30(7):366-73
19540807
J Clin Invest. 2007 May;117(5):1381-90
17446934
Neuroimmunomodulation. 2008;15(4-6):351-64
19047811
J Immunol. 1998 Jan 1;160(1):120-33
9551964
Trends Immunol. 2004 Nov;25(11):595-600
15489188
Eur J Immunol. 2001 Aug;31(8):2293-301
11477541
FASEB J. 2010 May;24(5):1340-6
20056718
Nat Rev Immunol. 2004 Nov;4(11):856-67
15516965
PLoS One. 2009 May 22;4(5):e5668
19479077
Mol Immunol. 2002 Mar;38(11):841-8
11922942
Gen Comp Endocrinol. 2008 Jul;157(3):266-74
18486132
Clin Exp Immunol. 2001 Sep;125(3):409-13
11531948
J Immunol. 2000 Feb 15;164(4):2180-7
10657672
Annu Rev Immunol. 2008;26:355-88
18304000
Nat Rev Immunol. 2009 Jan;9(1):57-62
19104499
J Endocrinol. 1993 Mar;136(3):389-97
8473828
Exp Cell Res. 2008 Oct 1;314(16):3027-35
18638475
Endocrinology. 2009 Sep;150(9):4163-9
19406942
Semin Immunol. 2007 Oct;19(5):318-30
18023361
J Clin Invest. 2009 Oct;119(10):3070-8
19770514
J Immunol. 2005 Aug 15;175(4):2741-53
16081852
J Steroid Biochem Mol Biol. 2010 May 31;120(2-3):69-75
20346397
Neuroimmunomodulation. 2008;15(4-6):290-322
19047807
J Immunol. 1989 Oct 1;143(7):2185-92
2550550
Endocrinology. 2005 Jun;146(6):2501-7
15731366
Endocr Rev. 2009 Dec;30(7):883-925
19887492