Estradiol Synthesis in Gut-Associated Lymphoid Tissue: Leukocyte Regulation by a Sexually Monomorphic System

• Published in: Endocrinology (Philadelphia) 2016-12, Vol.157 (12), p.4579-4587
• Main Authors: Oakley, Oliver R, Kim, Kee Jun, Lin, Po-Ching, Barakat, Radwa, Cacioppo, Joseph A, Li, Zhong, Whitaker, Alexandra, Chung, Kwang Chul, Mei, Wenyan, Ko, CheMyong
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Animals; Aromatase; Aromatase - genetics; Aromatase - metabolism; Brief Research Report; Cell culture; Estradiol - biosynthesis; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; Estrogen receptors; Estrogens; Female; Fluorescence; Gastrointestinal system; Gastrointestinal tract; Gonads; Gonads - metabolism; Gut-associated lymphoid tissues; Immunohistochemistry; Immunosurveillance; Leukocytes; Leukocytes - metabolism; Lymph nodes; Lymph Nodes - metabolism; Lymphoid tissue; Male; Mesentery - metabolism; Mice; Mice, Knockout; Organs; Peripheral blood; Peyer's Patches - metabolism; Protein biosynthesis; Red fluorescent protein; Reproductive system; Sex hormones; Spleen - metabolism; Synthesis; Tissue culture; Transgenic mice
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2016-1391

17β-estradiol is a potent sex hormone synthesized primarily by gonads in females and males that regulates development and function of the reproductive system. Recent studies show that 17β-estradiol is locally synthesized in nonreproductive tissues and regulates a myriad of events, including local inflammatory responses. In this study, we report that mesenteric lymph nodes (mLNs) and Peyer's patches (Pps) are novel sites of de novo synthesis of 17β-estradiol. These secondary lymphoid organs are located within or close to the gastrointestinal tract, contain leukocytes, and function at the forefront of immune surveillance. 17β-estradiol synthesis was initially identified using a transgenic mouse with red fluorescent protein coexpressed in cells that express aromatase, the enzyme responsible for 17β-estradiol synthesis. Subsequent immunohistochemistry and tissue culture experiments revealed that aromatase expression was localized to high endothelial venules of these lymphoid organs, and these high endothelial venule cells synthesized 17β-estradiol when isolated and cultured in vitro. Both mLNs and Pps contained 17β-estradiol with concentrations that were significantly higher than those of peripheral blood. Furthermore, the total amount of 17β-estradiol in these organs exceeded that of the gonads. Mice lacking either aromatase or estrogen receptor-β had hypertrophic Pps and mLNs with more leukocytes than their wild-type littermates, demonstrating a role for 17β-estradiol in leukocyte regulation. Importantly, we did not observe any sex-dependent differences in aromatase expression, 17β-estradiol content, or steroidogenic capacity in these lymphoid organs.