Estrogen deprivation and estrogen receptor α antagonism decrease DSS colitis in female mice
: Hjelt, Anja; Anttila, Santeri; Wiklund, Anu; Rokka, Anne; Al-Ramahi, Darin; Toivola, Diana M.; Polari, Lauri; Määttä, Jorma
Publisher: John Wiley & Sons
: 2024
: Pharmacology Research and Perspectives
: Pharmacology research & perspectives
: Pharmacol Res Perspect
: e1234
: 12
: 4
: 2052-1707
DOI: https://doi.org/10.1002/prp2.1234(external)
: https://research.utu.fi/converis/portal/detail/Publication/457131514(external)
The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium-induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200-fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo-oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation.
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This work has been supported by Business Finland (Former TEKES), decisions # 473/31/2015, 253/31/2019 and the Novo Nordisk Foundation, Pioneer Innovator Grant # NNF21OC0068904, Research Council of Finland 332582/315139, the InFLAMES Flagship Programme of the Research Council of Finland (337531 and 357911), Sigrid Juselius Foundation, Svenska Kulturfonden (187699), Victoriastiftelsen grant number 20240472, and Åbo Akademi University Centers of Excellence in Cellular Mechanostasis. We kindly thank Forendo Pharma Ltd (now Organon R&D Finland) for providing the experimental molecule SERM2. We acknowledge Heidi Liljenbäck at the Turku Center for Disease Modeling for the surgical procedures and post-operative care of the animals. We thank Merja Lakkisto and Joel Nyström for excellent technical assistance. Mass spectrometry analyses were performed at the Turku Center for Chemical and Molecular Analytics, Bioanalytical Laboratory and Turku Proteomics Facility, and University of Turku and Åbo Akademi University. The facilities are supported by Biocenter Finland.
