{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:33:34Z","timestamp":1791909214288,"version":"4.3.4"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["2017\/25\/B\/NZ5\/00819"],"award-info":[{"award-number":["2017\/25\/B\/NZ5\/00819"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["2018\/02\/X\/NZ5\/01357"],"award-info":[{"award-number":["2018\/02\/X\/NZ5\/01357"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dehydroepiandrosterone (DHEA) is an abundant steroid and precursor of sex hormones. During aging, the reduction in DHEA synthesis causes a significant depletion of estrogens and androgens in different organs, such as the ovaries, brain, and liver. Primary Biliary Cholangitis (PBC) is a cholestatic liver disease that begins with immune-mediated bile duct damage, and is followed by liver fibrosis, and finally, cirrhosis. PBC primarily affects postmenopausal women, with an average age of diagnosis of 65 years, but younger women are also affected. Here, we analyzed the levels of DHEA, estradiol (E2), and estriol (E3) in the PBC sera of females at an age of diagnosis under 40 (n = 37) and above 65 (n = 29). Our results indicate that in PBC patients at an age of diagnosis under 40, E2 was significantly lower compared to that in healthy women. In contrast, the levels of DHEA and E3 were in a normal range. Furthermore, ELISA assays revealed that in PBC patients at an age of diagnosis above 65, the levels of DHEA, E2, and E3 significantly declined in comparison to those in younger patients. In addition, flow cytometry analysis showed that the level of IL-8 significantly decreased while the level of TNF-\u03b1 increased in older PBC patients compared to younger ones. Moreover, we showed for the first time that the sulfonated form of DHEA, DHEA-S, reduces the levels of both pro-inflammatory interleukins, IL-8 and TNF-\u03b1, in PBC-like cholangiocytes (H69-miR506), while it diminishes the level of the pro-fibrotic interleukin, IL-13, in hepatocytes (Hep-G2). Finally, we demonstrated that the expression of the pro-fibrotic agent TGF-\u03b2 significantly increased in both the early (F0\u2013F3) and cirrhotic (F4) stages of PBC, and this elevation was accompanied by higher \u03b1-SMA expression.<\/jats:p>","DOI":"10.3390\/ijms24065301","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T02:30:33Z","timestamp":1678415433000},"page":"5301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["DHEA and Its Metabolites Reduce the Cytokines Involved in the Inflammatory Response and Fibrosis in Primary Biliary Cholangitis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5506-2397","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Blatkiewicz","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Poznan University of Medical Sciences, 61-781 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4272-2266","authenticated-orcid":false,"given":"Katarzyna","family":"Sielatycka","sequence":"additional","affiliation":[{"name":"Faculty of Exact and Natural Sciences, Institute of Biology, University of Szczecin, 70-415 Szczecin, Poland"},{"name":"Sanprobi Sp. z.o.o. Sp.k., 70-535 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-0830","authenticated-orcid":false,"given":"Katarzyna","family":"Piotrowska","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Kila\u0144czyk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/S0301-2115(02)00046-5","article-title":"Sex hormone profile and endometrial cancer risk in primary biliary cirrhosis: A case-control study","volume":"103","author":"Floreani","year":"2002","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1056\/NEJMra043898","article-title":"Primary biliary cirrhosis","volume":"353","author":"Kaplan","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.bbadis.2017.07.024","article-title":"Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology","volume":"1864","author":"Pinto","year":"2018","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41575-019-0125-y","article-title":"Cholangiocyte pathobiology","volume":"16","author":"Banales","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kilanczyk, E., Ruminkiewicz, D., Banales, J.M., Milkiewicz, P., and Milkiewicz, M. (2022). DHEA protects human cholangiocytes and hepatocytes against apoptosis and oxidative stress. Cells, 11.","DOI":"10.3390\/cells11061038"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"908468","DOI":"10.4061\/2011\/908468","article-title":"Recent advances in underlying pathologies provide insight into interleukin-8 expression-mediated inflammation and angiogenesis","volume":"2011","author":"Qazi","year":"2011","journal-title":"Int. J. Inflamm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/BF03401858","article-title":"Control of the proinflammatory state in cystic fibrosis lung epithelial cells by genes from the TNF-alphaR\/NFkappaB pathway","volume":"7","author":"Eidelman","year":"2001","journal-title":"Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1203\/01.PDR.0000076661.85928.1D","article-title":"Burkholderia cepacia-induced IL-8 gene expression in an alveolar epithelial cell line: Signaling through CD14 and mitogen-activated protein kinase","volume":"54","author":"Reddi","year":"2003","journal-title":"Pediatr. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1172\/JCI30542","article-title":"Models of liver fibrosis: Exploring the dynamic nature of inflammation and repair in a solid organ","volume":"117","author":"Iredale","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/hep.22934","article-title":"The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis","volume":"50","author":"Weng","year":"2009","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3389\/fimmu.2012.00116","article-title":"IL-13 Signaling in Liver Fibrogenesis","volume":"3","author":"Liu","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2174\/1568010043483944","article-title":"Estrogen, a double-edged sword: Modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1\/TH2 cytokine production","volume":"3","author":"Salem","year":"2004","journal-title":"Curr. Drug Targets-Inflamm. Allergy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103132","DOI":"10.1016\/j.jri.2020.103132","article-title":"Effects of Progesterone, Dydrogesterone and Estrogen on the Production of Th1\/Th2\/Th17 Cytokines by Lymphocytes from Women with Recurrent Spontaneous Miscarriage","volume":"140","author":"AbdulHussain","year":"2020","journal-title":"J. Reprod. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Harding, A.T., and Heaton, N.S. (2022). The Impact of Estrogens and Their Receptors on Immunity and Inflammation during Infection. Cancers, 14.","DOI":"10.3390\/cancers14040909"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.arcmed.2014.01.002","article-title":"Effect of estrogen on Th1, Th2 and Th17 cytokines production by proteolipid protein and PHA activated peripheral blood mononuclear cells isolated from multiple sclerosis patients","volume":"45","author":"Javadian","year":"2014","journal-title":"Arch. Med. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1053\/gast.2000.20184","article-title":"Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats","volume":"119","author":"Alvaro","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.jhep.2004.08.022","article-title":"Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis","volume":"41","author":"Alvaro","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.3748\/wjg.v12.i22.3537","article-title":"Estrogens and the pathophysiology of the biliary tree","volume":"12","author":"Alvaro","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1677\/joe.1.06264","article-title":"Is dehydroepiandrosterone a hormone?","volume":"187","author":"Labrie","year":"2005","journal-title":"J. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1007\/s40265-014-0259-8","article-title":"Dehydroepiandrosterone (DHEA): Hypes and hopes","volume":"74","author":"Rutkowski","year":"2014","journal-title":"Drugs"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1210\/endo-70-6-857","article-title":"Binding of dehydroepiandrosterone sulfate to serum albumin","volume":"70","author":"Puche","year":"1962","journal-title":"Endocrinology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"571353","DOI":"10.1155\/2015\/571353","article-title":"Liver Expression of Sulphotransferase 2A1 Enzyme Is Impaired in Patients with Primary Sclerosing Cholangitis: Lack of the Response to Enhanced Expression of PXR","volume":"2015","author":"Wunsch","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.neuint.2007.06.002","article-title":"Reduced plasma dehydroepiandrosterone sulfate levels are significantly correlated with fatigue severity in patients with primary biliary cirrhosis","volume":"52","author":"Ahboucha","year":"2008","journal-title":"Neurochem. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1111\/j.1365-2982.2009.01356.x","article-title":"Dehydroepiandrosterone sulphate improves cholestasis-associated fatigue in bile duct ligated rats","volume":"21","author":"Butterworth","year":"2009","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_25","first-page":"790","article-title":"Dehydroepiandrosterone sulfate indicates decreased sulfation capacity and impaired quality of life in patients with primary sclerosing cholangitis","volume":"131","author":"Wronka","year":"2021","journal-title":"Pol. Arch. Intern. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.yfrne.2008.04.001","article-title":"Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases","volume":"29","author":"Vegeto","year":"2008","journal-title":"Front. Neuroendocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1210\/er.2007-0001","article-title":"The complex role of estrogens in inflammation","volume":"28","author":"Straub","year":"2007","journal-title":"Endocr. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1189\/jlb.3A0914-430RR","article-title":"Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERalpha36 and GPR30\/GPER1","volume":"99","author":"Pelekanou","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1210\/clinem\/dgz196","article-title":"Sex-specific Estrogen Levels and Reference Intervals from Infancy to Late Adulthood Determined by LC-MS\/MS","volume":"105","author":"Frederiksen","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"729030","DOI":"10.3389\/fmed.2021.729030","article-title":"Testosterone and Estradiol as Novel Prognostic Indicators for HBV-Related Acute-on-Chronic Liver Failure","volume":"8","author":"Sun","year":"2021","journal-title":"Front. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/jgh.13182","article-title":"Low testosterone as a better predictor of mortality than sarcopenia in men with advanced liver disease","volume":"31","author":"Sinclair","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1365-2265.2012.04347.x","article-title":"Low testosterone levels as an independent predictor of mortality in men with chronic liver disease","volume":"77","author":"Grossmann","year":"2012","journal-title":"Clin. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1210\/endo-129-6-2933","article-title":"Tumor necrosis factor alpha inhibits gonadotropin action in cultured porcine Leydig cells: Site(s) of action","volume":"129","author":"Mauduit","year":"1991","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.3389\/fimmu.2019.02815","article-title":"Abnormal Expression of ERalpha in Cholangiocytes of Patients With Primary Biliary Cholangitis Mediated Intrahepatic Bile Duct Inflammation","volume":"10","author":"Cao","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1046\/j.1440-1746.2002.02672.x","article-title":"Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis","volume":"17","author":"Neuman","year":"2002","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s00281-022-00910-2","article-title":"TNF in the liver: Targeting a central player in inflammation","volume":"44","author":"Tiegs","year":"2022","journal-title":"Semin. Immunopathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.bbrc.2008.10.155","article-title":"TNFalpha is required for cholestasis-induced liver fibrosis in the mouse","volume":"378","author":"Gabele","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1128\/CDLI.9.4.802-807.2002","article-title":"Regulation of interleukin-8 by interleukin-10 and transforming growth factor beta in human monocytes infected with mycobacterium bovis","volume":"9","author":"Garcia","year":"2002","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jaut.2006.04.001","article-title":"Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis","volume":"26","author":"Chuang","year":"2006","journal-title":"J. Autoimmun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"829245","DOI":"10.3389\/fmed.2022.829245","article-title":"High Interleukin-8 Levels Associated With Decreased Survival in Patients With Cirrhosis Following Transjugular Intrahepatic Portosystemic Shunt","volume":"9","author":"Liu","year":"2022","journal-title":"Front. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Zimmermann, H.W., Seidler, S., Gassler, N., Nattermann, J., Luedde, T., Trautwein, C., and Tacke, F. (2011). Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021381"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1111\/liv.13316","article-title":"Association between serum soluble CD14 and IL-8 levels and clinical outcome in primary biliary cholangitis","volume":"37","author":"Umemura","year":"2017","journal-title":"Liver Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1002\/hep.29533","article-title":"MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation","volume":"67","author":"Erice","year":"2018","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"583","DOI":"10.3109\/08820139509066859","article-title":"Administration of dehydroepiandrosterone reverses the immune suppression induced by high dose antigen in mice","volume":"24","author":"Kim","year":"1995","journal-title":"Immunol. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.1210\/endo.139.7.6118","article-title":"Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: Independent effect from secondary weight reduction in genetically obese Zucker fatty rats","volume":"139","author":"Kimura","year":"1998","journal-title":"Endocrinology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1007\/s004030050213","article-title":"Dehydroepiandrosterone may be one of the regulators of cytokine production in atopic dermatitis","volume":"289","author":"Tabata","year":"1997","journal-title":"Arch. Dermatol. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1038\/mp.2017.167","article-title":"DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1\/2-CREB-Jmjd3 pathway","volume":"23","author":"Alexaki","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"R114","DOI":"10.1186\/cc7963","article-title":"DHEA-dependent and organ-specific regulation of TNF-alpha mRNA expression in a murine polymicrobial sepsis and trauma model","volume":"13","author":"Barkhausen","year":"2009","journal-title":"Crit. Care"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nm1332","article-title":"IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis","volume":"12","author":"Strober","year":"2006","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1128\/IAI.74.2.1215-1221.2006","article-title":"Cytokine production associated with periportal fibrosis during chronic schistosomiasis mansoni in humans","volume":"74","author":"Moreno","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s12931-022-02076-9","article-title":"Dehydroepiandrosterone in fibrotic interstitial lung disease: A translational study","volume":"23","author":"Guler","year":"2022","journal-title":"Respir. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"102187","DOI":"10.1016\/j.redox.2021.102187","article-title":"The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30","volume":"48","author":"Li","year":"2021","journal-title":"Redox Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5301\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:51:43Z","timestamp":1760122303000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,10]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065301"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065301","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,10]]}}}