Estradiol Inhibits Th17 Cell Differentiation through Inhibition of RORγT Transcription by Recruiting the ERα/REA Complex to Estrogen Response Elements of the RORγT Promoter

Abstract

The symptoms of vaginal candidiasis exacerbate in the second half of the menstrual cycle in the premenopausal women when the serum estradiol level is elevated. Estradiol has been shown to inhibit Th17 differentiation and production of antifungal interleukin-17 (IL-17) cytokines. However, little is known about the mechanisms. In the present study, we used mouse splenocytes and found that estradiol inhibited Th17 differentiation through down-regulation of Rorγt mRNA and protein expression. Estradiol activated ERα to recruit repressor of estrogen receptor activity (REA) and form ERα/REA complex. This complex bound to three estrogen response element (ERE) half-sites on the Rorγt promoter region to suppress Rorγt expression. Estradiol induced Rea mRNA and protein expression in mouse splenocytes. Using Rea siRNA to knockdown Rea expression enhanced Rorγt expression and Th17 differentiation. On the other hand, histone deacetylase (HDAC) 1 and 2 bound to the three ERE half-sites, independent of estradiol. HDAC inhibitor MS-275 dose- and time-dependently increased Rorγt expression, and subsequently enhanced Th17 differentiation. In 15 healthy premenopausal women, high serum estradiol levels are correlated with low RORγT mRNA levels and high REA mRNA levels in the vaginal lavage. These results demonstrate that estradiol up-regulates REA expression and recruits REA via ERα to the EREs on the RORγT promoter region, thus inhibiting RORγT expression and Th17 differentiation. This study suggests that the estradiol-ERα-REA axis may be a feasible target in the management of recurrent vaginal candidiasis.

Targeting Transcription Factor Lysine Acetylation in Inflammatory Airway Diseases

“…It was demonstrated that p300 acetylates RORγt at K81 (increasing its activity), whereas HDAC1 reduces acetylation of RORγt (which decreases its activity, although it was not studied which lysine was involved) in HEK293T cells and isolated naive T cells from healthy human subjects [105]. In line with this, MS-275 has been reported to enhance Th17 differentiation in mouse splenocytes [106]. On the other hand, the HDACi givinostat downregulated the IL-6 receptor on T cells which reduced their ability to differentiate into Th17 cells, but instead skewed differentiation toward the Treg phenotype [107].…”

“…Increased Treg suppressive function (in combination and alone) EX-527 increased acetylation of K31, K262 and K267, and increased the stability and levels of the transcription factor [91,96] Foxp3/Tregs HDAC1-3 inhibitor MS-275 Ambiguous effects [98][99][100] RORγt/Th17 HDAC1-3 inhibitor MS-275 Enhanced Th17 differentiation in mouse splenocytes [106] RORγt/Th17 Pan HDACi givinostat Downregulated the IL-6 receptor on T cells that reduced their ability to differentiate into Th17 cells, but instead skewed differentiation toward the Treg phenotype [107] Foxp3 and RORγt Pan HDACi TSA Increased Foxp3 and decreased RoRγt levels in an ovalbumin challenge asthma mouse model [38] HDAC: Histone deacetylase; HDACi: Histone deacetylase inhibitor; PBMC: Peripheral blood mononuclear cell; TSA: Trichostatin A.…”

“…This illustrates that individual HDACs have specific roles in the control of anti-inflammatory IL10 expression (with HDAC11 as an interesting possible target due to its inhibitory role in IL10 expression), and in the inhibition of CXCL8 expression by IL-10 in these cells. NF-κB/macrophages HDAC1-3 inhibitor MS-275 Ambiguous effects [66][67][68][69][70][71] NF-κB/macrophages HDAC3 inhibitor RGFP966 Attenuation of Inflammation [74] GATA3/Th2 cells SIRT1 inhibitor Sirtinol Increased Th2 related expression in T cells from cord blood; and in PBMCs from severe asthmatics Enhanced acetylation and activity of the GATA3 transcription factor in HUT78 T lymphocytes [83] GATA3/Th2 cells SIRT1 activator (SRT2172) Reduced IL-4 mRNA expression in PBMCs from ten patients with severe asthma [83] Foxp3/Tregs HDAC6i ACY-738 and SIRT1 inhibitor EX-527Increased Treg suppressive function (in combination and alone) EX-527 increased acetylation of K31, K262 and K267, and increased the stability and levels of the transcription factor [91,96] Foxp3/Tregs HDAC1-3 inhibitor MS-275 Ambiguous effects [98][99][100] RORγt/Th17 HDAC1-3 inhibitor MS-275 Enhanced Th17 differentiation in mouse splenocytes [106] RORγt/Th17 Pan HDACi givinostat Downregulated the IL-6 receptor on T cells that reduced their ability to differentiate into Th17 cells, but instead skewed differentiation toward the Treg phenotype [107] Foxp3 and RORγt Pan HDACi TSA Increased Foxp3 and decreased RoRγt levels in an ovalbumin challenge asthma mouse model [38] …”

Osteoimmunology: from mice to humans

“…9 In humans, a recent paper found no effect of estradiol in the secretion of IL-17 by T cells in patients affected by multiple sclerosis, 42 whereas another suggests that estradiol inhibited Th17 differentiation through downregulation of Rorgt mRNA and protein expression. 45 Nevertheless, in these studies, the effect of estradiol was evaluated in vitro on cells from patients not in menopause and in men. Hence, the results cannot be extended to women in menopause.…”

The vaginal mycobiome: A contemporary perspective on fungi in women's health and diseases

“…36,37 Some Candida species possess a cytosolic estrogen receptor that could mediate direct transcriptional responses to host hormones. 38 Furthermore, estrogen has been shown to disrupt neutrophil chemotaxis to the vaginal epithelium 39 and inhibit Th17 cell differentiation, 40 resulting in heightened host vulnerability to pathogens, such as Candida. Clinical and anecdotal reports frequently link symptomatic Candida vaginitis to the luteal phase, just prior to menses, which is marked by both a high estrogen state and increased vaginal pH.…”