GPR30 contributes to estrogen-induced thymic atrophy.
The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, reduce thymus weight, cellularity, and CD4 and CD8 phenotype expression, have not been well defined. In this study, the roles played by the membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), and the intracellular estrogen receptors, estrogen receptor alpha (ERalpha) and beta (ERbeta), in 17beta-estradiol (E2)-induced thymic atrophy were distinguished by construction and the side-by-side comparison of GPR30-deficient mice with ERalpha and ERbeta gene-deficient mice. Our study shows that whereas ERalpha mediated exclusively the early developmental blockage of thymocytes, GPR30 was indispensable for thymocyte apoptosis that preferentially occurs in T cell receptor beta chain(-/low) double-positive thymocytes. Additionally, G1, a specific GPR30 agonist, induces thymic atrophy and thymocyte apoptosis, but not developmental blockage. Finally, E2 treatment attenuates the activation of nuclear factor-kappa B in CD25(-)CD4(-)CD8(-) double-negative thymocytes through an ERalpha-dependent yet ERbeta- and GPR30-independent pathway. Differential inhibition of nuclear factor-kappaB by ERalpha and GPR30 might underlie their disparate physiological effects on thymocytes. Our study distinguishes, for the first time, the respective contributions of nuclear and membrane E2 receptors in negative regulation of thymic development.
Wang
Chunhe
C
Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA. wangch@ohsu.edu
Dehghani
Babak
B
Magrisso
I Jack
IJ
Rick
Elizabeth A
EA
Bonhomme
Edna
E
Cody
David B
DB
Elenich
Laura A
LA
Subramanian
Sandhya
S
Murphy
Stephanie J
SJ
Kelly
Martin J
MJ
Rosenbaum
Jan S
JS
Vandenbark
Arthur A
AA
Offner
Halina
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy / Q000139:chemically induced; D003517:Cyclopentanes / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology; D005260:Female; D007178:Inbreeding; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D003517:Cyclopentanes; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D016328:NF-kappa B; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol