Estradiol downregulates NF-κb translocation by Ikbkg transcriptional repression in dendritic cells

Abstract

To reconcile immunity and reproduction, females must allow spermatozoa to survive and control the presence of commensal microbiota and sexually transmitted pathogens during ovulation. Female steroid sex hormones exert a powerful effect on the immune system, as do the hormonal changes associated with the ovarian cycle. Dendritic cells (DCs) are immunological sentinels that link innate immunity to adaptive immunity. Upon exposure to microbial invaders in tissue, they undergo a maturational process that culminates in the lymph nodes and activates T-cell-specific immune responses. Estradiol, which is highly expressed during ovulation, has an effect on the maturation of DCs, although the molecular mechanism remains elusive. We detected that estradiol regulates expression of Ikbkg in DCs and modulates nuclear factor-κb translocation to the nucleus, thus explaining the reduced DC function observed during ovulation. This change may be an adaptive mechanism to reconcile control of infection and reproductive functions.

Sex Drives Dimorphic Immune Responses to Viral Infections

“…Although ERs can impact signaling pathways in ligand dependent and independent manners (62), signaling in immune cells is ligand dependent whereas signaling through coactivator-associated arginine methyltransferase (CARM)1 is ligand independent. E2 receptor (specifically ERα46 (63)), mediates anti-inflammatory signaling in monocytes and macrophages through suppression of CXC-motif ligand 8 (CXCL8) (63, 64). ERs activate STAT-signaling pathways during T and B cell proliferation, maintenance and activation.…”

Impact of in vitro treatments of physiological levels of estradiol and progesterone observed in pregnancy on bovine monocyte-derived dendritic cell differentiation and maturation

“…Suppression of the NF-κB pathway negatively impacts effective antigen presentation by DC (Yoshimura et al, 2001, Davies et al, 2004, Lasarte et al, 2013. Diminished DC maturation generated by E2 and PG likely promotes and maintains a viable, full term pregnancy by preventing the development of conceptus-derived antigen-specific responses .…”

“…Multiple factors in pregnancy have been shown to regulate various maternal immune cell populations; these cells may be regulated differently depending on the stage of pregnancy in order to meet the specific demands for successful implantation, maintenance of pregnancy, and preparation for parturition (Bauersachs and Wolf, 2013, Gomez-Lopez et al, 2014, Robertson and Moldenhauer, 2014. In murine and human models, the ability of DC to differentiate and mature can be altered by pregnancy-associated hormones, including estradiol (E2) and progesterone (PG), both of which are highly upregulated in pregnancy (Lamote et al, 2004, Segerer et al, 2009, Xu et al, 2011, Cordeau et al, 2012, Lasarte et al, 2013, Schumacher et al, 2014. The relationship of these two hormones, E2 and PG, appears to be complex and dependent on context and concentration.…”

“…The majority of studies show immunosuppressive effects of both E2 and PG on DC differentiation and maturation i.e. reduction in CD80 and MHC II, enhanced anti-inflammatory cytokine production with concurrent suppressed proinflammatory cytokine responses, and T cell stimulatory capacity (Hughes et al, 2008, Segerer et al, 2009, Jones et al, 2010, Xu et al, 2011, Lasarte et al, 2013. Both E2 and PG are relatively high in bovine late gestation relative to other stages of lactation, and in the case of E2, this hormone drastically increases as cows approach calving in the third trimester of pregnancy (Hunter et al, 1970, Echternkamp and Hansel, 1973, Smith et al, 1973.…”

Estrogen upregulates inflammatory signals through NF-κB, IFN-γ, and nitric oxide via Akt/mTOR pathway in the lymph node lymphocytes of middle-aged female rats

“…During aging, diminished percentage of antigen-presenting cells were found in the popliteal lymph nodes of old rats associated with immunosenescence [15]. Estrogen levels during ovulation have been shown to affect the maturation of dendritic cells and inhibit its functions in the lymph nodes by down-regulating NF-κB [16]. One of the key modulators of inflammation, NF-κB, is regulated by several pathways including PI3K, Akt, mammalian target of rapamycin (mTOR) pathway, thereby influencing cell growth, metabolism, growth, proliferation, survival, aging, synaptic plasticity, and memory [17,18].…”