title: Tissue-specific effect of estradiol on endothelial cell-dependent lymphocyte recruitment.
abstract: Estrogen profoundly affects onset and severity of many immune-mediated diseases. In our murine model of drug-induced autoimmunity, female-specific, estrogen-dependent increase in splenic lymphocyte homing was directly implicated in increased disease severity. The present study evaluated the effect of estradiol on microvascular endothelial cells from the spleen compared to endothelial cells from the dermis, which has no disease manifestation in this model. Estradiol increased spleen endothelial cell estrogen receptor (ER) alpha 2.9-fold and decreased estrogen receptor beta 2.1-fold while decreasing both receptors on dermal cells. Estradiol enhanced adhesion of D10 cells to spleen but not dermal endothelial cells 1.53-fold (P < 0.001), an increase that was inhibited by antibodies to VCAM-1 and ICAM-1, and by the estrogen receptor antagonists tamoxifen and ICI 182,780. Estradiol induced greater VCAM-1 expression on spleen than dermal endothelial cells (P < 0.05). Estradiol increased spleen endothelial cell estrogen receptor alpha 2.9-fold and decreased estrogen receptor beta 2.1-fold while decreasing both receptors on the dermal cells. Estrogen specifically and preferentially promoted spleen chemokine protein expression for MCP-1 and MCP-3, while having no effect on dermal protein expression for these chemokines. Estradiol-mediated effects on splenic chemokines were abrogated by tamoxifen and ICI 182,780. The gender-specific increase in lymphocyte homing to spleen may be attributable, at least in part, to tissue-specific estrogen-mediated effects on microvascular endothelial cells.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA. hsmurphy@umich.edu
authors.forename: Hedwig S
authors.initials: HS
authors.lastname: Murphy
authors.forename: Quan
authors.initials: Q
authors.lastname: Sun
authors.forename: Brian A
authors.initials: BA
authors.lastname: Murphy
authors.forename: RuRan
authors.initials: R
authors.lastname: Mo
authors.forename: Jirong
authors.initials: J
authors.lastname: Huo
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Chensue
authors.forename: Matthew
authors.initials: M
authors.lastname: Adams
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Richardson
authors.forename: Raymond
authors.initials: R
authors.lastname: Yung
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002448:Cell Adhesion; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054410:Chemokine CCL7; D018925:Chemokines / Q000096:biosynthesis; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000096:biosynthesis; D004967:Estrogens; D005260:Female; D005434:Flow Cytometry; D000077267:Fulvestrant; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D008833:Microcirculation; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012737:Sex Factors; D013154:Spleen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C515450:CCL7 protein, human; C515451:Ccl7 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D018925:Chemokines; D016207:Cytokines; D047629:Estrogen Receptor beta; D004967:Estrogens; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D019010:Vascular Cell Adhesion Molecule-1; D013629:Tamoxifen; D018799:Intercellular Adhesion Molecule-1; D000077267:Fulvestrant; D004958:Estradiol