17-β estradiol exerts anti-inflammatory effects through activation of Nrf2 in mouse embryonic fibroblasts
Several reports indicate crosstalk between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and estrogen, which has a protective effect in colorectal cancer (CRC). The aim of this study was to investigate the role of Nrf2 signaling in the anti-inflammatory effect of estrog...
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| description | Several reports indicate crosstalk between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and estrogen, which has a protective effect in colorectal cancer (CRC). The aim of this study was to investigate the role of Nrf2 signaling in the anti-inflammatory effect of estrogen using Nrf2 knockout (Nrf2 KO) mouse embryonic fibroblasts (MEFs), a powerful system to test the function of target genes due to their easy accessibility, and rapid growth rates. After inducing inflammation by tumor necrosis factor alpha (TNF-α), the effects of 17β-estradiol (E2) on the expression of proinflammatory mediators [i.e., NF-κB and inducible nitric oxide synthase (iNOS)] and estrogen receptors were evaluated by Western blot. In wild type (WT) MEFs, E2 treatment ameliorated TNF-α-induced nuclear translocation of NF-κB and expression of its target protein iNOS. Estrogen receptor beta (ERβ) expression was decreased by TNF-α-induced inflammation and restored by E2 treatment. When treated to WT MEFs, E2 induced nuclear translocation of Nrf2. The inhibitory effect of E2 on TNF-α-induced enhancement of iNOS was markedly dampened in Nrf2 KO MEFs. Notably, ERβ expression was significantly diminished in Nrf2 KO MEFs compared to that in WT cells. Promoter Database (EPD) revealed two putative anti-oxidant response elements (AREs) within the mouse ERβ promoter. Furthermore, in WT MEFs, E2 treatment repressed TNF-α-induced expression of iNOS protein and recovered by 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), a selective ERβ antagonist, treatment, but not in Nrf2 KO MEFs. In conclusion, Nrf2 plays a pivotal role in the anti-inflammatory of estrogen by direct regulating the expression of ERβ. |
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The aim of this study was to investigate the role of Nrf2 signaling in the anti-inflammatory effect of estrogen using Nrf2 knockout (Nrf2 KO) mouse embryonic fibroblasts (MEFs), a powerful system to test the function of target genes due to their easy accessibility, and rapid growth rates. After inducing inflammation by tumor necrosis factor alpha (TNF-α), the effects of 17β-estradiol (E2) on the expression of proinflammatory mediators [i.e., NF-κB and inducible nitric oxide synthase (iNOS)] and estrogen receptors were evaluated by Western blot. In wild type (WT) MEFs, E2 treatment ameliorated TNF-α-induced nuclear translocation of NF-κB and expression of its target protein iNOS. Estrogen receptor beta (ERβ) expression was decreased by TNF-α-induced inflammation and restored by E2 treatment. When treated to WT MEFs, E2 induced nuclear translocation of Nrf2. The inhibitory effect of E2 on TNF-α-induced enhancement of iNOS was markedly dampened in Nrf2 KO MEFs. Notably, ERβ expression was significantly diminished in Nrf2 KO MEFs compared to that in WT cells. Promoter Database (EPD) revealed two putative anti-oxidant response elements (AREs) within the mouse ERβ promoter. Furthermore, in WT MEFs, E2 treatment repressed TNF-α-induced expression of iNOS protein and recovered by 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), a selective ERβ antagonist, treatment, but not in Nrf2 KO MEFs. In conclusion, Nrf2 plays a pivotal role in the anti-inflammatory of estrogen by direct regulating the expression of ERβ.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0221650</identifier><identifier>PMID: 31442293</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>17β-Estradiol ; Animals ; Anti-Inflammatory Agents - pharmacology ; Antioxidants ; Biology and Life Sciences ; Colorectal cancer ; Colorectal carcinoma ; Crosstalk ; Cytokines ; Embryo fibroblasts ; Embryo, Mammalian - cytology ; Embryos ; Enzymes ; Estradiol - pharmacology ; Estrogen receptors ; Estrogens ; Female ; Fibroblasts ; Fibroblasts - cytology ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Genes ; Growth rate ; Inflammation ; Inflammatory bowel disease ; Inflammatory diseases ; Internal medicine ; Male ; Medicine ; Medicine and Health Sciences ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Biological ; NF-E2-Related Factor 2 - metabolism ; NF-kappa B - metabolism ; NF-κB protein ; Nitric oxide ; Nitric Oxide Synthase Type II - metabolism ; Nitric-oxide synthase ; Nuclear transport ; Oxidative stress ; Pharmacy ; Phenols ; Proteins ; Receptors ; Receptors, Estrogen - metabolism ; Regulatory sequences ; Research and Analysis Methods ; Sex hormones ; Stem cells ; Transcription factors ; Translocation ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-TNF ; Tumor necrosis factor-α</subject><ispartof>PloS one, 2019-08, Vol.14 (8), p.e0221650-e0221650</ispartof><rights>2019 Song et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Song et al 2019 Song et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-e6ae56472c9501933b22a216d297a1c41e688d36ae7b6506666e640a08cff8263</citedby><cites>FETCH-LOGICAL-c526t-e6ae56472c9501933b22a216d297a1c41e688d36ae7b6506666e640a08cff8263</cites><orcidid>0000-0002-9397-0406</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707591/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707591/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31442293$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Chin-Hee</creatorcontrib><creatorcontrib>Kim, Nayoung</creatorcontrib><creatorcontrib>Kim, Do-Hee</creatorcontrib><creatorcontrib>Lee, Ha-Na</creatorcontrib><creatorcontrib>Surh, Young-Joon</creatorcontrib><title>17-β estradiol exerts anti-inflammatory effects through activation of Nrf2 in mouse embryonic fibroblasts</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Several reports indicate crosstalk between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and estrogen, which has a protective effect in colorectal cancer (CRC). The aim of this study was to investigate the role of Nrf2 signaling in the anti-inflammatory effect of estrogen using Nrf2 knockout (Nrf2 KO) mouse embryonic fibroblasts (MEFs), a powerful system to test the function of target genes due to their easy accessibility, and rapid growth rates. After inducing inflammation by tumor necrosis factor alpha (TNF-α), the effects of 17β-estradiol (E2) on the expression of proinflammatory mediators [i.e., NF-κB and inducible nitric oxide synthase (iNOS)] and estrogen receptors were evaluated by Western blot. In wild type (WT) MEFs, E2 treatment ameliorated TNF-α-induced nuclear translocation of NF-κB and expression of its target protein iNOS. Estrogen receptor beta (ERβ) expression was decreased by TNF-α-induced inflammation and restored by E2 treatment. When treated to WT MEFs, E2 induced nuclear translocation of Nrf2. The inhibitory effect of E2 on TNF-α-induced enhancement of iNOS was markedly dampened in Nrf2 KO MEFs. Notably, ERβ expression was significantly diminished in Nrf2 KO MEFs compared to that in WT cells. Promoter Database (EPD) revealed two putative anti-oxidant response elements (AREs) within the mouse ERβ promoter. Furthermore, in WT MEFs, E2 treatment repressed TNF-α-induced expression of iNOS protein and recovered by 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), a selective ERβ antagonist, treatment, but not in Nrf2 KO MEFs. In conclusion, Nrf2 plays a pivotal role in the anti-inflammatory of estrogen by direct regulating the expression of ERβ.</description><subject>17β-Estradiol</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Antioxidants</subject><subject>Biology and Life Sciences</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Crosstalk</subject><subject>Cytokines</subject><subject>Embryo fibroblasts</subject><subject>Embryo, Mammalian - cytology</subject><subject>Embryos</subject><subject>Enzymes</subject><subject>Estradiol - pharmacology</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Genes</subject><subject>Growth rate</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Inflammatory diseases</subject><subject>Internal medicine</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Models, Biological</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Nitric oxide</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Nitric-oxide synthase</subject><subject>Nuclear transport</subject><subject>Oxidative stress</subject><subject>Pharmacy</subject><subject>Phenols</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Regulatory sequences</subject><subject>Research and Analysis Methods</subject><subject>Sex hormones</subject><subject>Stem cells</subject><subject>Transcription factors</subject><subject>Translocation</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumor necrosis factor-α</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUstu1DAUjRCIlsIfILDEhk0Gv2InG6Sq4lGpgg2sLce5nvHIsQc7qZjf6of0m_AwadUivLHle-7xPcenql4TvCJMkg_bOKeg_WoXA6wwpUQ0-El1SjpGa0Exe_rgfFK9yHmLccNaIZ5XJ4xwTmnHTqstkfXtDYI8JT246BH8hjRlpMPkahes1-Oop5j2CKwFUyrTJsV5vUHaTO5aTy4GFC36lixFLqAxzhkQjH3ax-AMsq5Psfc6T_ll9cxqn-HVsp9VPz9_-nHxtb76_uXy4vyqNg0VUw1CQyO4pKZrcFHAekp1UTfQTmpiOAHRtgMrKNkXyaIsEBxr3BprWyrYWfX2yLvzMavFpqwold3BJiIL4vKIGKLeql1yo057FbVTfy9iWiudJmc8KMGbhhFDKO45J0OnrTRAcN8azHtKaOH6uLw29yMMBkJx0j8ifVwJbqPW8VoJiWXTkULwfiFI8ddcPkKNLhvwXgcoZpa524ZgKvgB-u4f6P_V8SPKpJhzAns_DMHqEJ27LnWIjlqiU9rePBRy33SXFfYHiubCcw</recordid><startdate>20190823</startdate><enddate>20190823</enddate><creator>Song, Chin-Hee</creator><creator>Kim, Nayoung</creator><creator>Kim, Do-Hee</creator><creator>Lee, Ha-Na</creator><creator>Surh, Young-Joon</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-9397-0406</orcidid></search><sort><creationdate>20190823</creationdate><title>17-β estradiol exerts anti-inflammatory effects through activation of Nrf2 in mouse embryonic fibroblasts</title><author>Song, Chin-Hee ; Kim, Nayoung ; Kim, Do-Hee ; Lee, Ha-Na ; Surh, Young-Joon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-e6ae56472c9501933b22a216d297a1c41e688d36ae7b6506666e640a08cff8263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>17β-Estradiol</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Antioxidants</topic><topic>Biology and Life Sciences</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Crosstalk</topic><topic>Cytokines</topic><topic>Embryo fibroblasts</topic><topic>Embryo, Mammalian - cytology</topic><topic>Embryos</topic><topic>Enzymes</topic><topic>Estradiol - pharmacology</topic><topic>Estrogen receptors</topic><topic>Estrogens</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Genes</topic><topic>Growth rate</topic><topic>Inflammation</topic><topic>Inflammatory bowel disease</topic><topic>Inflammatory diseases</topic><topic>Internal medicine</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Models, Biological</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>NF-kappa B - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Chin-Hee</au><au>Kim, Nayoung</au><au>Kim, Do-Hee</au><au>Lee, Ha-Na</au><au>Surh, Young-Joon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>17-β estradiol exerts anti-inflammatory effects through activation of Nrf2 in mouse embryonic fibroblasts</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-08-23</date><risdate>2019</risdate><volume>14</volume><issue>8</issue><spage>e0221650</spage><epage>e0221650</epage><pages>e0221650-e0221650</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Several reports indicate crosstalk between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and estrogen, which has a protective effect in colorectal cancer (CRC). The aim of this study was to investigate the role of Nrf2 signaling in the anti-inflammatory effect of estrogen using Nrf2 knockout (Nrf2 KO) mouse embryonic fibroblasts (MEFs), a powerful system to test the function of target genes due to their easy accessibility, and rapid growth rates. After inducing inflammation by tumor necrosis factor alpha (TNF-α), the effects of 17β-estradiol (E2) on the expression of proinflammatory mediators [i.e., NF-κB and inducible nitric oxide synthase (iNOS)] and estrogen receptors were evaluated by Western blot. In wild type (WT) MEFs, E2 treatment ameliorated TNF-α-induced nuclear translocation of NF-κB and expression of its target protein iNOS. Estrogen receptor beta (ERβ) expression was decreased by TNF-α-induced inflammation and restored by E2 treatment. When treated to WT MEFs, E2 induced nuclear translocation of Nrf2. The inhibitory effect of E2 on TNF-α-induced enhancement of iNOS was markedly dampened in Nrf2 KO MEFs. Notably, ERβ expression was significantly diminished in Nrf2 KO MEFs compared to that in WT cells. Promoter Database (EPD) revealed two putative anti-oxidant response elements (AREs) within the mouse ERβ promoter. Furthermore, in WT MEFs, E2 treatment repressed TNF-α-induced expression of iNOS protein and recovered by 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), a selective ERβ antagonist, treatment, but not in Nrf2 KO MEFs. In conclusion, Nrf2 plays a pivotal role in the anti-inflammatory of estrogen by direct regulating the expression of ERβ.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31442293</pmid><doi>10.1371/journal.pone.0221650</doi><orcidid>https://orcid.org/0000-0002-9397-0406</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 17β-Estradiol Animals Anti-Inflammatory Agents - pharmacology Antioxidants Biology and Life Sciences Colorectal cancer Colorectal carcinoma Crosstalk Cytokines Embryo fibroblasts Embryo, Mammalian - cytology Embryos Enzymes Estradiol - pharmacology Estrogen receptors Estrogens Female Fibroblasts Fibroblasts - cytology Fibroblasts - drug effects Fibroblasts - metabolism Genes Growth rate Inflammation Inflammatory bowel disease Inflammatory diseases Internal medicine Male Medicine Medicine and Health Sciences Mice, Inbred C57BL Mice, Knockout Models, Biological NF-E2-Related Factor 2 - metabolism NF-kappa B - metabolism NF-κB protein Nitric oxide Nitric Oxide Synthase Type II - metabolism Nitric-oxide synthase Nuclear transport Oxidative stress Pharmacy Phenols Proteins Receptors Receptors, Estrogen - metabolism Regulatory sequences Research and Analysis Methods Sex hormones Stem cells Transcription factors Translocation Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-TNF Tumor necrosis factor-α |
| title | 17-β estradiol exerts anti-inflammatory effects through activation of Nrf2 in mouse embryonic fibroblasts |
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