Reproduction and Fertility Linked to the Estradiol’s Regulation of NF-κb Translocation in Dendritic Cells

estradiol and NFkb dendritic cells

A new study published in Genes & Immunity may explain why some immune responses, and particularly dendritic cells (DCs) functions are restrained during ovulation.

The menstrual cycle is related to subtle changes in sex hormone levels (see Cover Image) that may have, however, profound effects on innate and adaptive immune responses.

Estradiol levels, which are low during the first half of the menstrual cycle, rise and peak 2–3 days before ovulation.

During ovulation, humoral and cell-mediated immune responses are believed to be suppressed in order to provide optimal conditions for procreation.

However, in the normal menstrual cycle, this may be related to a ‘window of vulnerability’ (C.R. Wira & J.V. Fahey, AIDS, 2008, 22: 1909) beginning at ovulation and lasting 7–10 days, in which females are more susceptible to infections of the female reproductive tract (FRT), including Candida albicans, genital herpes simplex virus, Chlamydia trachomatis and HIV.

In the human FRT, sperm is ‘stored’ for many days, i.e. fertilization occurs when intercourse takes place up to 6 days before ovulation (A. Wilcox et al., N Engl J Med, 1995; 333:1517).

Thus, the above-mentioned time-frame is also considered to be causally related to an ‘immune tolerance’ to the allogeneic sperm, and allows semen to survive during ovulation and during this ‘window of opportunity and tolerance’ to increase the chance of fertilization. This phenomenon and the overall hormonal control of FRT’s infections and reproductive functions remain unclear.

The Genes & Immunity study by S. Lasarte et al. from the Hospital General Universitario Gregorio Marañón, Madrid, Spain, provides, however, new insights into these mechanisms.

The authors of this study demonstrate that estradiol is able to suppress the NF-κb translocation to the nucleus, a step crucial for the dendritic cells maturation process, by its transcriptional downregulation of Ikbkg expression at the promoter level in DCs.

This may explain the reduced DCs’ function observed during ovulation. The authors suggest that estradiol–inhibited DCs would not trigger the maturation program, migrate to the T-cell areas and upregulate antigen presentation proteins during estrus (high estradiol) so that spermatozoa can survive.

Therefore, allogeneic spermatozoa could reach and be stored at the oviduct in order to acquire the ability to fertilize. According to the authors, DCs are ‘shutdown’ due this hormone-driven adaptive mechanism that may bring together the female immune response with reproductive function.

These findings may also be related to the inhibitory effects of estrus levels of estradiol on sperm-induced Th17 responses recently reported by the same research group.

Source: Genes Immun, 2013, 14:462-9. doi: 10.1038/gene.2013.35. Epub 2013 Jul 25.

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