title: The selective estrogen receptor modulators, tamoxifen and raloxifene, impair dendritic cell differentiation and activation.
abstract: Most immune cells, including myeloid progenitors and terminally differentiated dendritic cells (DC), express estrogen receptors (ER) making these cells sensitive to estrogens. Our laboratory recently demonstrated that 17-beta-estradiol (E2) promotes the GM-CSF-mediated development of CD11c+ CD11b(int) DC from murine bone marrow precursors. We tested whether the therapeutic selective estrogen receptor modulators (SERM), raloxifene and tamoxifen, can perturb DC development and activation. SERM, used in treatment of breast cancer and osteoporosis, bind to ER and mediate tissue-specific agonistic or antagonistic effects. Raloxifene and tamoxifen inhibited the differentiation of estrogen-dependent DC from bone marrow precursors ex vivo in competition experiments with physiological levels of E2. DC differentiated in the presence of SERM were assessed for their capacity to internalize fluoresceinated Ags as well as respond to inflammatory stimuli by increasing surface expression of molecules important for APC function. Although SERM-exposed DC exhibited increased ability to internalize Ags, they were hyporesponsive to bacterial LPS: relative to control DC, they less efficiently up-regulated the expression of MHC class II, CD86, and to a lesser extent, CD80 and CD40. This phenotype indicates that these SERM act to maintain DC in an immature state by inhibiting DC responsiveness to inflammatory stimuli. Thus, raloxifene and tamoxifen impair E2-promoted DC differentiation and reduce the immunostimulatory capacity of DC. These observations suggest that SERM may depress immunity when given to healthy individuals for the prevention of osteoporosis and breast cancer and may interfere with immunotherapeutic strategies to improve antitumor immunity in breast cancer patients.
authors.affiliation: Division of Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Nalbandian
authors.forename: Vladislava
authors.initials: V
authors.lastname: Paharkova-Vatchkova
authors.forename: Allen
authors.initials: A
authors.lastname: Mao
authors.forename: Stephanie
authors.initials: S
authors.lastname: Nale
authors.forename: Susan
authors.initials: S
authors.lastname: Kovats
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D008297:Male; D051379:Mice; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D020845:Selective Estrogen Receptor Modulators; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol