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.