Estrogen deprivation and estrogen receptor α antagonism decrease DSS colitis in female mice.
Animals
Female
Estrogen Receptor alpha
/ metabolism
Dextran Sulfate
Colitis
/ chemically induced
Mice
Estradiol
/ pharmacology
Ovariectomy
Mice, Inbred C57BL
Estrogens
/ pharmacology
Cyclooxygenase 2
/ metabolism
Disease Models, Animal
Interleukin-17
/ metabolism
Colon
/ pathology
Interleukin-6
/ metabolism
Interleukin-1beta
/ metabolism
colitis
dextran sulfate
estradiol
estrogen
estrogen receptor modulators
inflammatory bowel diseases
receptors
Journal
Pharmacology research & perspectives
ISSN: 2052-1707
Titre abrégé: Pharmacol Res Perspect
Pays: United States
ID NLM: 101626369
Informations de publication
Date de publication:
Aug 2024
Aug 2024
Historique:
revised:
27
05
2024
received:
26
03
2024
accepted:
11
06
2024
medline:
4
7
2024
pubmed:
4
7
2024
entrez:
4
7
2024
Statut:
ppublish
Résumé
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.
Substances chimiques
Estrogen Receptor alpha
0
Dextran Sulfate
9042-14-2
Estradiol
4TI98Z838E
Estrogens
0
Cyclooxygenase 2
EC 1.14.99.1
Esr1 protein, mouse
0
Interleukin-17
0
Interleukin-6
0
Interleukin-1beta
0
Il17a protein, mouse
0
Ptgs2 protein, mouse
EC 1.14.99.-
IL1B protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1234Subventions
Organisme : Svenska Kulturfonden
ID : 187699
Organisme : Business Finland
ID : 253/31/2019
Organisme : Business Finland
ID : 473/31/2015
Organisme : Victoriastiftelsen
ID : 20240472
Organisme : Research Council of Finland
ID : 315139
Organisme : Research Council of Finland
ID : 332582
Organisme : Novo Nordisk Fonden
ID : NNF21OC0068904
Organisme : InFLAMES Flagship Programme of the Academy of Finland
ID : 337531
Organisme : InFLAMES Flagship Programme of the Academy of Finland
ID : 357911
Informations de copyright
© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
Références
Chang JT. Pathophysiology of inflammatory bowel diseases. N Engl J Med. 2020;383(27):2652‐2664. doi:10.1056/NEJMra2002697
Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(1):56‐66. doi:10.1038/s41575-020-00360-x
Straub RH. The complex role of estrogens in inflammation. Endocr Rev. 2007;28(5):521‐574. doi:10.1210/er.2007-0001
Wang R, Li Z, Liu S, Zhang D. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the global burden of disease study 2019. BMJ Open. 2023;13(3):e065186. doi:10.1136/bmjopen-2022-065186
Shah SC, Khalili H, Gower‐Rousseau C, et al. Sex‐based differences in incidence of inflammatory bowel diseases—pooled analysis of population‐based studies from Western countries. Gastroenterology. 2018;155(4):1079‐1089. doi:10.1053/J.GASTRO.2018.06.043
Ortizo R, Lee SY, Nguyen ET, Jamal MM, Bechtold MM, Nguyen DL. Exposure to oral contraceptives increases the risk for development of inflammatory bowel disease: a meta‐analysis of case‐controlled and cohort studies. Eur J Gastroenterol Hepatol. 2017;29(9):1064‐1070. doi:10.1097/MEG.0000000000000915
Pasvol TJ, Bloom S, Segal AW, Rait G, Horsfall L. Use of contraceptives and risk of inflammatory bowel disease: a nested case‐control study summary background: how contraceptive formulation, dose, duration of therapy and mode. Aliment Pharmacol Ther. 2022;55:318‐326. doi:10.1111/apt.16647
Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol. 2015;294(2):63‐69. doi:10.1016/j.cellimm.2015.01.018
Hoffmann JP, Liu JA, Seddu K, Klein SL. Sex hormone signaling and regulation of immune function. Immunity. 2023;56(11):2472‐2491. doi:10.1016/J.IMMUNI.2023.10.008
Pierdominici M, Maselli A, Varano B, et al. Linking estrogen receptor β expression with inflammatory bowel disease activity. Oncotarget. 2015;6(38):40443‐40451. doi:10.18632/ONCOTARGET.6217
Linares PM, Algaba A, Urzainqui A, et al. Ratio of circulating estrogen receptors Beta and Alpha (ERβ/ERα) indicates endoscopic activity in patients with Crohn's disease. Dig Dis Sci. 2017;62(10):2744‐2754. doi:10.1007/S10620-017-4717-5/FIGURES/4
Li H, Chen H, Chen L, Shen D, Xu X. Expression of oestrogen receptor beta was negatively correlated with disease activity in patients with Crohn's disease involving the terminal ileum. Steroids. 2019;141:36‐40. doi:10.1016/J.STEROIDS.2018.09.013
Jacenik D, Cygankiewicz AI, Mokrowiecka A, Małecka‐Panas E, Fichna J, Krajewska WM. Sex‐ and age‐related estrogen signaling alteration in inflammatory bowel diseases: modulatory role of estrogen receptors. Int J Mol Sci. 2019;20(13):1‐18. doi:10.3390/IJMS20133175
Bábíčková J, Tóthová Ľ, Lengyelová E, et al. Sex differences in experimentally induced colitis in mice: a role for estrogens. Inflammation. 2015;38(5):1996‐2006. doi:10.1007/s10753-015-0180-7
Song CH, Kim N, Sohn SH, et al. Effects of 17β‐estradiol on colonic permeability and inflammation in an azoxymethane/dextran sulfate sodium‐induced colitis mouse model. Gut Liver. 2018;12(6):682‐693. doi:10.5009/GNL18221
Heijmans J, Wielenga MCB, Rosekrans SL, et al. Oestrogens promote tumorigenesis in a mouse model for colitis‐associated cancer. Gut. 2014;63(2):310‐316. doi:10.1136/GUTJNL-2012-304216
Calippe B, Douin‐Echinard V, Laffargue M, et al. Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: involvement of the phosphatidylinositol 3‐kinase pathway. J Immunol. 2008;180(12):7980‐7988.
Goodman WA, Havran HL, Quereshy HA, Kuang S, De Salvo C, Pizarro TT. Estrogen receptor α loss‐of‐function protects female mice from DSS‐induced experimental colitis. Cell Mol Gastroenterol Hepatol. 2018;5(4):630‐633. doi:10.1016/J.JCMGH.2017.12.003
Gao X, Fan W, Tan L, et al. Soy isoflavones ameliorate experimental colitis by targeting ERα/NLRP3 inflammasome pathways. J Nutr Biochem. 2020;83:108438. doi:10.1016/J.JNUTBIO.2020.108438
Riggs BL, Hartmann LC. Drug therapy selective estrogen‐receptor modulators‐mechanisms of action and application to clinical practice. N Engl J Med. 2003;348:618‐629.
Chadwick CC, Chippari S, Matelan E, et al. Identification of pathway‐selective estrogen receptor ligands that inhibit NF‐κB transcriptional activity. Proc Natl Acad Sci USA. 2005;102(7):2543‐2548. doi:10.1073/PNAS.0405841102/SUPPL_FILE/05841TABLE3.HTML
Greish K, Taha S, Jasim A, et al. Styrene maleic acid encapsulated raloxifene micelles for management of inflammatory bowel disease. Clin Transl Med. 2017;6(1):e28. doi:10.1186/S40169-017-0157-2
Bebo BF, Dehghani B, Foster S, Kurniawan A, Lopez FJ, Sherman LS. Treatment with selective estrogen receptor modulators regulates myelin specific T‐cells and suppresses experimental autoimmune encephalomyelitis. Glia. 2009;57(7):777‐790. doi:10.1002/GLIA.20805
Elloso MM, Phiel K, Henderson RA, Harris HA, Adelman SJ. Suppression of experimental autoimmune encephalomyelitis using estrogen receptor‐selective ligands. J Endocrinol. 2005;185(2):243‐252. doi:10.1677/JOE.1.06063
Jeong H, Kim IY, Bae EK, Jeon CH, Ahn KS, Cha HS. Selective estrogen receptor modulator lasofoxifene suppresses spondyloarthritis manifestation and affects characteristics of gut microbiota in zymosan‐induced SKG mice. Sci Rep. 2021;11(1):1‐12. doi:10.1038/s41598-021-91320-1
Cushman M, Costantino JP, Tracy RP, et al. Tamoxifen and cardiac risk factors in healthy women. Arterioscler Thromb Vasc Biol. 2001;21(2):255‐261. doi:10.1161/01.ATV.21.2.255
Katsandegwaza B, Horsnell W, Smith K. Inflammatory bowel disease: a review of pre‐clinical murine models of human disease. Int J Mol Sci. 2022;23(16):1‐19. doi:10.3390/IJMS23169344
Polari L, Wiklund A, Sousa S, et al. SERMs promote anti‐inflammatory signaling and phenotype of CD14+ cells. Inflammation. 2018;41(4):1157‐1171. doi:10.1007/s10753-018-0763-1
Polari L, Anttila S, Helenius T, et al. Novel selective estrogen receptor modulator ameliorates murine colitis. Int J Mol Sci. 2019;20(12):1‐14. doi:10.3390/ijms20123007
ten Hove T, van den Blink B, Pronk I, Drillenburg M, Peppelenbosch MP, van Deventer SJH. Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis. Gut. 2002;50:507‐512. doi:10.1136/gut.50.4.507
Schindelin J, Arganda‐Carreras I, Frise E, et al. Fiji: an open‐source platform for biological‐image analysis. Nat Methods. 2012;9(7):676‐682. doi:10.1038/nmeth.2019
Bankhead P, Loughrey MB, Fernández JA, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7(1):16878. doi:10.1038/s41598-017-17204-5
Harding SD, Sharman JL, Faccenda E, et al. The IUPHAR/BPS guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Res. 2018;46(D1):D1091‐D1106. doi:10.1093/NAR/GKX1121
Alexander SPH, Cidlowski JA, Kelly E, et al. The concise guide to PHARMACOLOGY 2023/24: nuclear hormone receptors. Br J Pharmacol. 2023;180(S2):S223‐S240. doi:10.1111/BPH.16179
Hases L, Indukuri R, Birgersson M, et al. Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes. Cancer Lett. 2020;492:54‐62. doi:10.1016/J.CANLET.2020.06.021
Fan W, Ding C, Liu S, et al. Estrogen receptor β activation inhibits colitis by promoting NLRP6‐mediated autophagy. Cell Rep. 2022;41(2):111454. doi:10.1016/J.CELREP.2022.111454
Pettersson K, Delaunay F, Gustafsson JA. Estrogen receptor β acts as a dominant regulator of estrogen signaling. Oncogene. 2000;19(43):4970‐4978. doi:10.1038/SJ.ONC.1203828
Lindberg MK, Movérare S, Skrtic S, et al. Estrogen receptor (ER)‐β reduces ERα‐regulated gene transcription, supporting a “Ying Yang” relationship between ERα and ERβ in mice. Mol Endocrinol. 2003;17(2):203‐208. doi:10.1210/ME.2002-0206
Weihua Z, Saji S, Mäkinen S, et al. Estrogen receptor (ER) β, a modulator of ERα in the uterus. Proc Natl Acad Sci U S A. 2000;97(11):5936‐5941. doi:10.1073/PNAS.97.11.5936
Petz LN, Ziegler YS, Schultz JR, Kim H, Kemper JK, Nardulli AM. Differential regulation of the human progesterone receptor gene through an estrogen response element half site and Sp1 sites. J Steroid Biochem Mol Biol. 2004;88:113‐122. doi:10.1016/j.jsbmb.2003.11.008
Spitz IM, Bardin CW. Mifepristone (RU 486)—a modulator of progestin and glucocorticoid action. N Engl J Med. 1993;329(6):404‐412.
Zakharova M, Ziegler HK. Paradoxical anti‐inflammatory actions of TNF‐α: inhibition of IL‐12 and IL‐23 via TNF receptor 1 in macrophages and dendritic cells. J Immunol. 2005;175(8):5024‐5033. doi:10.4049/JIMMUNOL.175.8.5024
Steeland S, Libert C, Vandenbroucke RE. A new venue of TNF targeting. Int J Mol Sci. 2018;19(5):1442. doi:10.3390/IJMS19051442
Wei HX, Wang B, Li B. IL‐10 and IL‐22 in mucosal immunity: driving protection and pathology. Front Immunol. 2020;11:548633. doi:10.3389/FIMMU.2020.01315/BIBTEX
Brazil M. Oestrogen activates COX2 pathway. Nat Rev Drug Discov. 2005;4(1):16. doi:10.1038/nrd1615
Tamura M, Deb S, Sebastian S, Okamura K, Bulun SE. Estrogen up‐regulates cyclooxygenase‐2 via estrogen receptor in human uterine microvascular endothelial cells. Fertil Steril. 2004;81(5):1351‐1356. doi:10.1016/j.fertnstert.2003.09.076
Zhang J, Chen C. Endocannabinoid 2‐arachidonoylglycerol protects neurons by limiting COX‐2 elevation. J Biol Chem. 2008;283(33):22601‐22611. doi:10.1074/JBC.M800524200
Ishikawa TO, Oshima M, Herschman HR. Cox‐2 deletion in myeloid and endothelial cells, but not in epithelial cells, exacerbates murine colitis. Carcinogenesis. 2011;32(3):417‐426. doi:10.1093/CARCIN/BGQ268
Villablanca AC, Hanley MR. 17β‐estradiol stimulates substance P receptor gene expression. Mol Cell Endocrinol. 1997;135(2):109‐117. doi:10.1016/S0303-7207(97)00193-7
Okamura H, Yokosuka M, Hayashi S. Induction of substance P‐immunoreactivity by estrogen in neurons containing estrogen receptors in the Anterovental periventricular nucleus of female but not male rats. J Neuroendocrinol. 1994;6(6):609‐615. doi:10.1111/J.1365-2826.1994.TB00626.X
García‐Ortega J, Pinto FM, Prados N, et al. Expression of tachykinins and tachykinin receptors and interaction with kisspeptin in human granulosa and cumulus cells. Biol Reprod. 2016;94(6):124‐125. doi:10.1095/BIOLREPROD.116.139881/2863883
Tavano F, di Mola FF, Latiano A, et al. Neuroimmune interactions in patients with inflammatory bowel diseases: disease activity and clinical behavior based on substance P serum levels. J Crohns Colitis. 2012;6(5):563‐570. doi:10.1016/J.CROHNS.2011.11.004
Patel M, Subas SV, Ghani MR, et al. Role of substance P in the pathophysiology of inflammatory bowel disease and its correlation with the degree of inflammation. Cureus. 2020;12(10):e11027. doi:10.7759/CUREUS.11027
Renzi D, Pellegrini B, Tonelli F, Surrenti C, Calabro A. Substance P (neurokinin‐1) and neurokinin a (neurokinin‐2) receptor gene and protein expression in the healthy and inflamed human intestine. Am J Pathol. 2000;157(5):1511‐1522. doi:10.1016/S0002-9440(10)64789-X
Khalili H, Higuchi LM, Ananthakrishnan AN, et al. Hormone therapy increases risk of ulcerative colitis but not Crohn's disease. Gastroenterology. 2012;143(5):1199‐1206. doi:10.1053/J.GASTRO.2012.07.096
Wang Q, Li Z, Liu K, et al. Activation of the G protein‐coupled estrogen receptor prevented the development of acute colitis by protecting the crypt cell. J Pharmacol Exp Ther. 2021;376(2):281‐293. doi:10.1124/jpet.120.000216
Prossnitz ER, Barton M. The G protein‐coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol. 2023;19(7):407‐424. doi:10.1038/s41574-023-00822-7