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

17 beta-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 17 beta-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 17 beta-estradiol. These secondary lymphoid organs are located within or close to the gastrointestinal tract, contain leukocytes, and function at the forefront of immune surveillance. 17 beta-estradiol synthesis was initially identified using a transgenic mouse with red fluorescent protein coexpressed in cells that express aromatase, the enzyme responsible for 17 beta-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 17 beta-estradiol when isolated and cultured in vitro. Both mLNs and Pps contained 17 beta-estradiol with concentrations that were significantly higher than those of peripheral blood. Furthermore, the total amount of 17 beta-estradiol in these organs exceeded that of the gonads. Mice lacking either aromatase or estrogen receptor-beta had hypertrophic Pps and mLNs with more leukocytes than their wild-type littermates, demonstrating a role for 17 beta-estradiol in leukocyte regulation. Importantly, we did not observe any sex-dependent differences in aromatase expression, 17 beta-estradiol content, or steroidogenic capacity in these lymphoid organs.