Abstract
Female sex steroids, estradiol (E2) and progesterone (P4), play a key role in regulating immune responses in women, including dendritic cell (DC) development, and functions. Although the two hormones co-occur in the body of women throughout the reproductive years, no studies have explored their complex combinatorial effects on DCs, given their ability to regulate each other’s actions. We examined murine bone marrow derived dendritic cells (BMDC) differentiation and functions, in the presence of a wide range of physiological concentrations of each hormone, as well as the combination of the two hormones. E2 (10−12 to 10-8M) enhanced the differentiation of CD11b+CD11c+ DCs from BM precursor cells, and promoted the expression of CD40 and MHC Class-II, in a dose-dependent manner. In contrast, P4 (10−9 to 10-5M) inhibited DC differentiation, but only at the highest concentrations. These effects on BMDCs were observed both in the presence or absence of LPS. When both hormones were combined, higher concentrations of P4, at levels seen in pregnancy (10-6M) reversed the E2 effects, regardless of the concentration of E2, especially in the absence of LPS. Functionally, antigen uptake was decreased and pro-inflammatory cytokines, IL-12, IL-1 and IL-6 production by CD11b+CD11c+ DCs, was increased in the presence of E2 and these effects were reversed by high concentrations of P4. Our results demonstrate the distinct effects of E2 and P4 on differentiation and functions of bone marrow myeloid DCs. The dominating effect of higher physiological concentrations of P4 provides insight into how DC functions could be modulated during pregnancy.
Highlights
Dendritic cells (DCs) play a central role in both innate and acquired immune responses [1] [2]
To exclude the possibility that the change in percentages was due to alterations in total number of viable cells, we calculated the number of CD11b+CD11c+ DCs at day 6 of the bone marrow derived dendritic cells (BMDC) culture, using viable cell counts from those cultures
In concurrence with the effects seen on the proportion of BMDCs, the effects of E2 on absolute DC numbers were significant as well (p
Summary
Dendritic cells (DCs) play a central role in both innate and acquired immune responses [1] [2]. Under non-inflammatory conditions, tissue DCs are relatively immature in their ability to initiate adaptive immune responses Because of their location at the internal and external body surface, and their ability to endocytose and process antigens from invading pathogens, the tissue DCs play a critical role during innate responses, as first responders to infection, and subsequently, following activation and migration to tissue-draining lymph nodes in directing and coordinating T cell responses. It follows, that altered physiologic conditions, such as hormonal changes, stress, or injury can likely alter both the differentiation of DCs and their immune functions
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