Estrogen Preferentially Promotes the Differentiation of CD11c+ CD11bintermediate Dendritic Cells from Bone Marrow Precursors

Paharkova-Vatchkova, Vladislava; Maldonado, Ruben; Kovats, Susan

doi:10.4049/jimmunol.172.3.1426

Cited by 216 publications

(198 citation statements)

References 65 publications

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“…This suggests that androgen might play a role in protecting male mice from the development of CIA. Estrogen has been shown to influence the immune response by influencing B cell survival and modulating dendritic cell function (25,26). We observed a higher number of B cells in female mice, even though the difference did not reach statistical significance.…”

Section: Discussionmentioning

confidence: 37%

New humanized HLA–DR4–transgenic mice that mimic the sex bias of rheumatoid arthritis

Taneja¹,

Behrens²,

Mangalam³

et al. 2007

Arthritis & Rheumatism

100

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Objective. To generate a mouse model that can mimic human rheumatoid arthritis (RA). A major difference between RA in humans and collagen-induced arthritis (CIA) in mice is the lack of sex bias and autoantibodies in the animal model. We used DRB1*0401-transgenic mice to understand the role of DR4 in susceptibility and sex bias in RA.Methods. A transgenic mouse was generated that lacked all endogenous mouse class II genes (AE o ) and expressed the RA susceptibility allele HLA-DRB1*0401. These transgenic mice were tested for incidence, severity, and sex distribution of CIA.Results. DRB1*0401.AE o mice developed CIA predominantly in females and produced rheumatoid factors, similar to the features of human RA. Another feature similar to human RA is the expression of class II molecules on antigen-presenting cells as well as T cells. Activated and sorted CD4؉ T cells can present DR4-restricted type II collagen (CII)-derived peptide in vitro, but cannot process the antigen. This suggests a role for these cells in epitope presentation locally in joints, which affects disease severity. After challenge with CII, female mice had higher cellularity and increased T cell proliferation and produced higher levels of proinflammatory cytokines than did the male mice.Conclusion. DR4.AE o mice expressed HLA similar to humans and displayed increased arthritis susceptibility in females, thus mimicking RA in humans. This model may be valuable for studying sex differences observed in humans and for understanding why autoimmunity is increased in women. These mice may also be useful for developing future therapeutic strategies.

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Section: Discussionmentioning

confidence: 37%

New humanized HLA–DR4–transgenic mice that mimic the sex bias of rheumatoid arthritis

Taneja¹,

Behrens²,

Mangalam³

et al. 2007

Arthritis & Rheumatism

100

View full text Add to dashboard Cite

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“…We previously demonstrated that physiological amounts (0.1 nM) of 17␤-estradiol (E2) promote the GM-CSF-mediated differentiation of DC from BM progenitors in ex vivo cultures derived from either female or male mice (29). Our experiments with the ER antagonist ICI 182,780, selective ER modulators, and ER␣ Ϫ/Ϫ BM cells indicated that estrogen acts via the ER to promote DC differentiation (29,30 …”

Section: Angerhans Cells (Lc)mentioning

confidence: 99%

“…Our experiments with the ER antagonist ICI 182,780, selective ER modulators, and ER␣ Ϫ/Ϫ BM cells indicated that estrogen acts via the ER to promote DC differentiation (29,30 …”

Section: Angerhans Cells (Lc)mentioning

confidence: 99%

Estrogen Selectively Promotes the Differentiation of Dendritic Cells with Characteristics of Langerhans Cells

Mao¹,

Paharkova-Vatchkova²,

Hardy

et al. 2005

The Journal of Immunology

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The steroid hormone estrogen regulates the differentiation, survival, or function of diverse immune cells. Previously, we found that physiological amounts of 17β-estradiol act via estrogen receptors (ER) to promote the GM-CSF-mediated differentiation of dendritic cells (DC) from murine bone marrow progenitors in ex vivo cultures. Of the two major subsets of CD11c+ DC that develop in these cultures, estrogen is preferentially required for the differentiation of a CD11bintLy6C− population, although it also promotes increased numbers of a CD11bhighLy6C+ population. Although both DC subsets express ERα, only the CD11bhighLy6C+ DC express ERβ, perhaps providing a foundation for the differential regulation of these two DC types by estrogen. The two DC populations exhibit distinct phenotypes in terms of capacity for costimulatory molecule and MHC expression, and Ag internalization, which predict functional differences. The CD11bintLy6C− population shows the greatest increase in MHC and CD86 expression after LPS activation. Most notably, the estrogen-dependent CD11bintLy6C− DC express langerin (CD207) and contain Birbeck granules characteristic of Langerhans cells. These data show that estrogen promotes a DC population with the unique features of epidermal Langerhans cells and suggest that differentiation of Langerhans cells in vivo will be dependent upon local estrogen levels and ER-mediated signaling events in skin.

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“…Based on competition experiments with 17-␤-estradiol (E2), it was concluded that SERM were not operating through ER because E2 was not found to counteract the inhibitory effects of SERM on DC phenotype. Our own studies have shown that the development of murine bone marrow-derived DC (BMDC) from GM-CSF-stimulated precursors in vitro was promoted by the presence of E2 in the culture medium (31). Differentiation of BMDC from E2-supplemented cultures was inhibited in the presence of a molar excess of the full ER antagonist, ICI 182,780, and tamoxifen.…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

The Selective Estrogen Receptor Modulators, Tamoxifen and Raloxifene, Impair Dendritic Cell Differentiation and Activation

Nalbandian

Paharkova-Vatchkova

Mao

et al. 2005

The Journal of Immunology

Self Cite

106

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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-β-estradiol (E2) promotes the GM-CSF-mediated development of CD11c+CD11bint 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.

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Estrogen Preferentially Promotes the Differentiation of CD11c+ CD11bintermediate Dendritic Cells from Bone Marrow Precursors

Cited by 216 publications

References 65 publications

New humanized HLA–DR4–transgenic mice that mimic the sex bias of rheumatoid arthritis

New humanized HLA–DR4–transgenic mice that mimic the sex bias of rheumatoid arthritis

Estrogen Selectively Promotes the Differentiation of Dendritic Cells with Characteristics of Langerhans Cells

The Selective Estrogen Receptor Modulators, Tamoxifen and Raloxifene, Impair Dendritic Cell Differentiation and Activation

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