Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells

Komi, Janne; Lassila, O.

doi:10.1182/blood.v95.9.2875.009k12_2875_2882

Cited by 115 publications

(64 citation statements)

References 47 publications

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“…DC, which suggests other drugs can be employed to modify DC for treatment of autoimmune disorders [44,45]. In evaluating immunosuppressants, Dex, rapamycin and FK506, commonly used in clinical practice for developing tolerogenic DC, in line with the previous studies [25,26], we found that Dex induced development of CD1a -DC derived from human peripheral monocytes (Fig.…”

Section: Discussionsupporting

confidence: 81%

Dexamethasone Induces IL‐10‐Producing Monocyte‐Derived Dendritic Cells with Durable Immaturity

et al. 2005

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It is highly desirable that immature dendritic cells (DC) used for tolerance induction maintain steady immature state with predominant interleukin (IL)-10 production. In this study, we attempted to develop DC with durable immaturity and other tolerogenic features by using dexamethasone (Dex). We found DC derived from human monocytes in the presence of 10 À7 M Dex were negative for CD1a. Compared with control transduced DC (Ctrl-DC), Dex-DC expressed lower CD40, CD80 and CD86 but equivalent human leucocyte antigen-DR. Both immature Dex-and Ctrl-DC did not express CD83. Nevertheless, upon stimulation of lipopolysaccharide (LPS) or CD40 ligand, the expression of CD40, CD80, CD83 and CD86 was upregulated on Ctrl-DC but not on Dex-DC. The immaturity of Dex-DC was durable following Dex removal. Interestingly, Dex-DC maintained production of large amount of IL-10 and little IL-12 five days after Dex removed. Further study indicated that high-level IL-10 production by Dex-DC was associated with high-level phosphorylation of extracellular signal-regulated kinase (ERK) as blockade of this enzyme markedly attenuated IL-10 production. Furthermore, Dex-DC sustained the capability of high phosphorylation of ERK and IL-10 production 5 days after Dex removal. In addition, Dex-DC had significantly lower activity in stimulating T-cell proliferation. Neutralization of IL-10, to some extent, promoted DC maturation activated by LPS, as well as T-cell stimulatory activity of Dex-DC. The above findings suggest that IL-10-producing Dex-DC with durable immaturity are potentially useful for induction of immune tolerance.

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Section: Discussionsupporting

confidence: 81%

Dexamethasone Induces IL‐10‐Producing Monocyte‐Derived Dendritic Cells with Durable Immaturity

et al. 2005

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“…The endocrine system participates in regulating the differentiation and maturation of different DC subtypes, e.g., thyroid-stimulating hormone induces a stimulatory effect on phagocytosis and cytokine production in murine DCs (47). In addition, mRNAs for estrogen receptor-␣ and -␤ have been demonstrated in CD14 ϩ monocytes, cultured immature CD1a ϩ cells, and mature CD83 ϩ cells (48). In culture, bone marrow progenitors give rise to the generation of DCs (49), which can be influenced by the action of androgens and estrogens (48,50).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, mRNAs for estrogen receptor-␣ and -␤ have been demonstrated in CD14 ϩ monocytes, cultured immature CD1a ϩ cells, and mature CD83 ϩ cells (48). In culture, bone marrow progenitors give rise to the generation of DCs (49), which can be influenced by the action of androgens and estrogens (48,50). Moreover, glucocorticoids inhibit the in vitro differentiation of DCs from their progenitors and impair their capacity to undergo terminal differentiation or generate proinflammatory cytokines (17).…”

Section: Discussionmentioning

confidence: 99%

Control of dendritic cell maturation and function by triiodothyronine

et al. 2007

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Accumulating evidence indicates a functional crosstalk between immune and endocrine mechanisms in the modulation of innate and adaptive immunity. However, the impact of thyroid hormones (THs) in the initiation of adaptive immune responses has not yet been examined. Here we investigated the presence of thyroid hormone receptors (TRs) and the impact of THs in the physiology of mouse dendritic cells (DCs), specialized antigen-presenting cells with the unique capacity to fully activate naive T cells and orchestrate adaptive immunity. Both immature and lipopolysaccharide-matured bone marrow-derived DCs expressed TRs at mRNA and protein levels, showing a preferential cytoplasmic localization. Remarkably, physiological levels of triiodothyronine (T3) stimulated the expression of DC maturation markers (major histocompatibility complex II, CD80, CD86, and CD40), markedly increased the secretion of interleukin-12, and stimulated the ability of DCs to induce naive T cell proliferation and IFN-gamma production in allogeneic T cell cultures. Analysis of the mechanisms involved in these effects revealed the ability of T3 to influence the cytoplasmic-nuclear shuttling of nuclear factor-kappaB on primed DCs. Our study provides the first evidence for the presence of TRs on bone marrow-derived DCs and the ability of THs to regulate DC maturation and function. These results have profound implications in immunopathology, including cancer and autoimmune manifestations of the thyroid gland at the crossroads of the immune and endocrine systems.

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“…42,43 The possibility of modulating DC function with certain SERMs has also been evaluated. The antiestrogens tamoxifen and toremifene 44,45 as well as raloxifene 27 are able to inhibit the differentiation and maturation of DCs. While this capacity could possibly be exploited in the treatment of autoimmune diseases it might, on the other hand, interfere with useful immune responses in association with breast cancer treatment or prevention of osteoporosis with tamoxifen or toremifene 44,45 and raloxifene, respectively.…”

Section: Regulation Of Cells Of the Monocyte-macrophage System With Smentioning

confidence: 99%

Monocyte–Macrophage System as a Target for Estrogen and Selective Estrogen Receptor Modulators

Härkönen

Väänänen

2006

Annals of the New York Academy of Sciences

106

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Postmenopausal decline of estrogen production is associated with development of several degenerative disorders such as osteoporosis, neuroinflammatory diseases and vascular wall degeneration. These are associated with the activation of the cells of the monocyte-macrophage system in a context-dependent manner. Estrogen regulates differentiation, maturation and function of many cell types in this system directly or indirectly via other cells by autocrine/paracrine mechanisms. Estrogen effects on the monocyte-macrophage system are primarily repressive. Most of these effects are mediated by repression of expression of genes for cytokines or modulation of other inflammatory mediators by the estrogen receptor (ER)-dependent or nongenomic pathways. The ER-dependent mechanisms mostly involve modulation of the nuclear factor kappa B (NF-kappaB) pathway for transcriptional regulation of cytokine or other mediator genes. In the context of hormone-regulated cancer, estrogen can influence production of cytokines or other inflammatory mediators by both tumor cells and tumor-invading macrophages. The interactions of breast and prostate cancer cells with tumor-associated macrophages (TAMs) may play an important role in tumor progression and even in the development of resistance to hormonal treatment. Regulation of the monocyte-macrophage system by estrogen and cross-talk between the ER and cytokine-mediated pathways provides multiple novel targets for development of selective ER modulator (SERM) molecules for prevention and treatment of postmenopausal degenerative and neoplastic diseases.

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Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells

Cited by 115 publications

References 47 publications

Dexamethasone Induces IL‐10‐Producing Monocyte‐Derived Dendritic Cells with Durable Immaturity

Dexamethasone Induces IL‐10‐Producing Monocyte‐Derived Dendritic Cells with Durable Immaturity

Control of dendritic cell maturation and function by triiodothyronine

Monocyte–Macrophage System as a Target for Estrogen and Selective Estrogen Receptor Modulators

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