Inhibitory effects of progesterone differ in dendritic cells from female and male rodents - PubMed (original) (raw)

Inhibitory effects of progesterone differ in dendritic cells from female and male rodents

Cherié L Butts et al. Gend Med. 2008 Dec.

Abstract

Background: Steroid hormones, such as progesterone, are known to have immunomodulatory effects. Our research group previously reported direct effects of progesterone on dendritic cells (DCs) from female rodents. Primarily affecting mature DC function, progesterone effects included inhibition of proinflammatory cytokine secretion, downregulation of cell surface marker (major histocompatibility complex class II, CD80) expression, and decreased T-cell proliferative capacity, and were likely mediated through progesterone receptor (PR) because the PR antagonist RU486 reversed these effects.

Objective: The goal of this study was to assess differences in response to progesterone by DCs from female and male rodents.

Methods: Using real-time reverse-transcriptase polymerase chain reaction, transcriptional expression of steroid hormone receptors was measured in immature bone marrow-derived DCs (BMDCs) from male and female rats. Expression of steroid hormone receptor protein was also assessed in these cells using flow cytometry and fluorescence microscopy. To evaluate functional differences between BMDCs from female and male rats in response to the steroid hormone progesterone, levels of secreted cytokines were measured using enzyme-linked immunosorbent assay.

Results: Higher numbers of immature BMDCs from males expressed glucocorticoid receptor (GR) and androgen receptor (AR) proteins compared with females (males vs females, mean [SD]: GR = 68.75 [7.27] vs 43.61 [13.97], P = NS; AR = 75.99 [15.38] vs 8.25 [1.88], P = 0.002), whereas higher numbers of immature BMDCs from females expressed PR protein compared with males (females vs males: PR = 74.19 [12.11] vs 14.14 [4.55], P = 0.043). These differences were not found at the level of transcription (females vs males: GR = 0.088 vs 0.073, P = NS; AR = 0.076 vs 0.069, P = NS; PR = 0.075 vs 0.065, P = NS). Compared with those from females, mature BMDCs from males produced higher quantities of cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta, IL-10) (females vs males: TNF-alpha = 920.0 [79.25] vs 1100.61 [107.97], P = NS; IL-1beta = 146.60 [38.04] vs 191.10 [10.47], P = NS; IL-10 = 167.25 [4.50] vs 206.15 [23.48], P = NS). Conversely, BMDCs from females were more sensitive to progesterone, as indicated by a more dramatic reduction in proinflammatory cytokine secretion (females vs males, highest concentration of progesterone: TNF-alpha = 268.94 [28.59] vs 589.91 [100.98], P = 0.04; IL-1beta = 119.50 [10.32] vs 154.35 [6.22], P = NS).

Conclusions: These findings suggest that progesterone effects on DCs in rodents may be more pronounced in females than in males, and this is likely due to differences in PR protein expression. Our observations may help elucidate disparities in the incidence and severity of autoimmune disorders between females and males, and the role specific steroid hormones play in regulating immune responses.

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Figures

Figure 1

Figure 1

Transcriptional expression of steroid hormone receptor by immune cells from female and male rats (n = 9 each). Total RNA from cultured cells was isolated and analyzed for expression of the steroid hormone receptor genes for glucocorticoid (GR), androgen (AR), and progesterone (PR). Total RNA from CD11 c+ dendritic cells (DCs) and T lymphocytes was also isolated from splenic tissue for comparison to bone marrow–derived DCs (BMDCs). Values are presented as the mean (SO) of the relative fold induction of the specified gene.

Figure 2

Figure 2

Expression of steroid hormone receptor protein by immature bone marrow–derived dendritic cells (BMDCs) from female and male rats (n = 7 each). (A) Representative histograms show proportions of immature BMDCs expressing receptors for glucocorticoid (GR), androgen (AR), and progesterone (PR). (B) Representative fluorescent micrographs show immature BMDC expression of steroid hormone receptor (red) and were counterstained (blue) with DAPI (4′-6-diamidino-2-phenylindole) to identify nuclei of cells.

Figure 3

Figure 3

Production of proinflammatory cytokine tumor necrosis factor-α by lipopolysaccharide (LPS)-stimulated bone marrow–derived dendritic cells from female and male rats (n = 8 each). Cells were stimulated to maturity with LPS and treated with progesterone or a combination of progesterone and the progesterone receptor antagonist RU486. Values are presented as mean (SD). *p ≤ 0.05 versus LPS alone.

Figure 4

Figure 4

Production of proinflammatory cytokine interleukin-1β by lipopolysaccharide (LPS)-stimulated bone marrow–derived dendritic cells from female and male rats (n = 8 each). Cells were stimulated to maturity with LPS and treated with progesterone or a combination of progesterone and the progesterone receptor antagonist RU486. Values are presented as mean (SD). *p ≤ 0.05 versus LPS alone.

Figure 5

Figure 5

Production of T-helper 2 response-promoting cytokine interleukin-10 by lipopolysaccharide (LPS)-stimulated bone marrow–derived dendritic cells from female and male rats (n = 6 each). Cells were stimulated to maturity with LPS and treated with progesterone or a combination of progesterone and the progesterone receptor antagonist RU486. Values are presented as mean (SD).

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