17-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-
estradiol is locally synthesized in non-reproductive tissues and regulates a myriad of events, including
local inflammatory responses. In this study, we report that mesenteric lymph nodes and
Peyer’s patches are novel sites of de novo synthesis of 17-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-estradiol synthesis was initially identified using a
transgenic mouse with red fluorescent protein co-expressed in cells that express aromatase, the
enzyme responsible for 17-estradiol synthesis. Subsequent immunohistochemistry and tissue culture
experiments revealed aromatase expression was localized to high endothelial venules (HEVs)
of these lymphoid organs, and these HEV cells synthesized 17-estradiol when isolated and cultured
in vitro. Both the mesenteric lymph nodes and Peyer’s patches contained 17-estradiol with
concentrations that were significantly higher than those of peripheral blood. Furthermore, the
total amount of 17-estradiol in these organs exceeded that of the gonads. Mice lacking either
aromatase or estrogen receptor beta (ER) had hypertrophic Peyer’s patches and mesenteric lymph
nodes withmoreleukocytes than their wild type littermates, demonstrating a role for 17-estradiol
in leukocyte regulation. Importantly, we did not observe any sex-dependent differences in aromatase
expression, 17-estradiol content, or steroidogenic capacity in these lymphoid organs.