CD69 is a TGF-β/1α,25-dihydroxyvitamin D3 target gene in monocytes
CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regu...
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| description | CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH)2D3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ∼2.3 kb promoter fragments by TGF-β and 1α,25(OH)2D3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3'UTR reporter construct showed that TGF-β and 1α,25(OH)2D3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH)2D3 on mRNA level, although different mechanisms account for the upregulation of each gene. |
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In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH)2D3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ∼2.3 kb promoter fragments by TGF-β and 1α,25(OH)2D3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3'UTR reporter construct showed that TGF-β and 1α,25(OH)2D3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH)2D3 on mRNA level, although different mechanisms account for the upregulation of each gene.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0064635</identifier><identifier>PMID: 23696902</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3' Untranslated regions ; Activation ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Antigens, Differentiation, T-Lymphocyte - genetics ; Antigens, Differentiation, T-Lymphocyte - metabolism ; Arachidonate 5-lipoxygenase ; Biology ; Blotting, Western ; CD69 antigen ; Cell Line ; Cell Line, Tumor ; Cell lines ; Cloning ; Comparative studies ; Cytokines ; Deoxyribonucleic acid ; DNA ; Gene expression ; Gene regulation ; Growth factors ; Humans ; Inflammation ; Kinases ; Lectins, C-Type - genetics ; Lectins, C-Type - metabolism ; Leukemia ; Leukotrienes ; Lipoxygenase ; Lymphocytes B ; MAP kinase ; Monocytes ; Monocytes - drug effects ; Monocytes - metabolism ; mRNA stability ; Penicillin ; Pharmaceuticals ; Plasmids ; Polymerase Chain Reaction ; Regulatory mechanisms (biology) ; Signal transduction ; Signaling ; Smad3 protein ; Stability analysis ; Stimuli ; TAK1 protein ; Transcription ; Transcription factors ; Transforming growth factor ; Transforming Growth Factor beta - pharmacology ; Transforming growth factor-b ; Vitamin D ; Vitamin D - analogs & derivatives ; Vitamin D - pharmacology ; Vitamin D3</subject><ispartof>PloS one, 2013-05, Vol.8 (5), p.e64635-e64635</ispartof><rights>2013 Wöbke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>2013 Wöbke et al 2013 Wöbke et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4415-ec3473091167f7f8f5becaf788adefa67c5245828d1c29d27a50547d9abe17703</citedby><cites>FETCH-LOGICAL-c4415-ec3473091167f7f8f5becaf788adefa67c5245828d1c29d27a50547d9abe17703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655964/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655964/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23696902$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Sanchez-Margalet, Victor</contributor><creatorcontrib>Wöbke, Thea K</creatorcontrib><creatorcontrib>von Knethen, Andreas</creatorcontrib><creatorcontrib>Steinhilber, Dieter</creatorcontrib><creatorcontrib>Sorg, Bernd L</creatorcontrib><title>CD69 is a TGF-β/1α,25-dihydroxyvitamin D3 target gene in monocytes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH)2D3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ∼2.3 kb promoter fragments by TGF-β and 1α,25(OH)2D3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3'UTR reporter construct showed that TGF-β and 1α,25(OH)2D3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH)2D3 on mRNA level, although different mechanisms account for the upregulation of each gene.</description><subject>3' Untranslated regions</subject><subject>Activation</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Antigens, Differentiation, T-Lymphocyte - genetics</subject><subject>Antigens, Differentiation, T-Lymphocyte - metabolism</subject><subject>Arachidonate 5-lipoxygenase</subject><subject>Biology</subject><subject>Blotting, Western</subject><subject>CD69 antigen</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cloning</subject><subject>Comparative studies</subject><subject>Cytokines</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>Lectins, C-Type - genetics</subject><subject>Lectins, C-Type - metabolism</subject><subject>Leukemia</subject><subject>Leukotrienes</subject><subject>Lipoxygenase</subject><subject>Lymphocytes B</subject><subject>MAP kinase</subject><subject>Monocytes</subject><subject>Monocytes - drug effects</subject><subject>Monocytes - metabolism</subject><subject>mRNA stability</subject><subject>Penicillin</subject><subject>Pharmaceuticals</subject><subject>Plasmids</subject><subject>Polymerase Chain Reaction</subject><subject>Regulatory mechanisms (biology)</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Smad3 protein</subject><subject>Stability analysis</subject><subject>Stimuli</subject><subject>TAK1 protein</subject><subject>Transcription</subject><subject>Transcription factors</subject><subject>Transforming growth factor</subject><subject>Transforming Growth Factor beta - pharmacology</subject><subject>Transforming growth factor-b</subject><subject>Vitamin D</subject><subject>Vitamin D - 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genetics</topic><topic>Antigens, CD - metabolism</topic><topic>Antigens, Differentiation, T-Lymphocyte - genetics</topic><topic>Antigens, Differentiation, T-Lymphocyte - metabolism</topic><topic>Arachidonate 5-lipoxygenase</topic><topic>Biology</topic><topic>Blotting, Western</topic><topic>CD69 antigen</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell lines</topic><topic>Cloning</topic><topic>Comparative studies</topic><topic>Cytokines</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Gene expression</topic><topic>Gene regulation</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Kinases</topic><topic>Lectins, C-Type - genetics</topic><topic>Lectins, C-Type - metabolism</topic><topic>Leukemia</topic><topic>Leukotrienes</topic><topic>Lipoxygenase</topic><topic>Lymphocytes B</topic><topic>MAP kinase</topic><topic>Monocytes</topic><topic>Monocytes - drug effects</topic><topic>Monocytes - metabolism</topic><topic>mRNA stability</topic><topic>Penicillin</topic><topic>Pharmaceuticals</topic><topic>Plasmids</topic><topic>Polymerase Chain Reaction</topic><topic>Regulatory mechanisms (biology)</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Smad3 protein</topic><topic>Stability analysis</topic><topic>Stimuli</topic><topic>TAK1 protein</topic><topic>Transcription</topic><topic>Transcription factors</topic><topic>Transforming growth factor</topic><topic>Transforming Growth Factor beta - pharmacology</topic><topic>Transforming growth factor-b</topic><topic>Vitamin D</topic><topic>Vitamin D - analogs & derivatives</topic><topic>Vitamin D - pharmacology</topic><topic>Vitamin D3</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wöbke, Thea K</creatorcontrib><creatorcontrib>von Knethen, Andreas</creatorcontrib><creatorcontrib>Steinhilber, Dieter</creatorcontrib><creatorcontrib>Sorg, Bernd L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Proquest Nursing & Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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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>Wöbke, Thea K</au><au>von Knethen, Andreas</au><au>Steinhilber, Dieter</au><au>Sorg, Bernd L</au><au>Sanchez-Margalet, Victor</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD69 is a TGF-β/1α,25-dihydroxyvitamin D3 target gene in monocytes</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-05-16</date><risdate>2013</risdate><volume>8</volume><issue>5</issue><spage>e64635</spage><epage>e64635</epage><pages>e64635-e64635</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH)2D3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ∼2.3 kb promoter fragments by TGF-β and 1α,25(OH)2D3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3'UTR reporter construct showed that TGF-β and 1α,25(OH)2D3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH)2D3 on mRNA level, although different mechanisms account for the upregulation of each gene.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23696902</pmid><doi>10.1371/journal.pone.0064635</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1352868961 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 3' Untranslated regions Activation Antigens, CD - genetics Antigens, CD - metabolism Antigens, Differentiation, T-Lymphocyte - genetics Antigens, Differentiation, T-Lymphocyte - metabolism Arachidonate 5-lipoxygenase Biology Blotting, Western CD69 antigen Cell Line Cell Line, Tumor Cell lines Cloning Comparative studies Cytokines Deoxyribonucleic acid DNA Gene expression Gene regulation Growth factors Humans Inflammation Kinases Lectins, C-Type - genetics Lectins, C-Type - metabolism Leukemia Leukotrienes Lipoxygenase Lymphocytes B MAP kinase Monocytes Monocytes - drug effects Monocytes - metabolism mRNA stability Penicillin Pharmaceuticals Plasmids Polymerase Chain Reaction Regulatory mechanisms (biology) Signal transduction Signaling Smad3 protein Stability analysis Stimuli TAK1 protein Transcription Transcription factors Transforming growth factor Transforming Growth Factor beta - pharmacology Transforming growth factor-b Vitamin D Vitamin D - analogs & derivatives Vitamin D - pharmacology Vitamin D3 |
| title | CD69 is a TGF-β/1α,25-dihydroxyvitamin D3 target gene in monocytes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-10T12%3A49%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=CD69%20is%20a%20TGF-%CE%B2/1%CE%B1,25-dihydroxyvitamin%20D3%20target%20gene%20in%20monocytes&rft.jtitle=PloS%20one&rft.au=W%C3%B6bke,%20Thea%20K&rft.date=2013-05-16&rft.volume=8&rft.issue=5&rft.spage=e64635&rft.epage=e64635&rft.pages=e64635-e64635&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0064635&rft_dat=%3Cproquest_plos_%3E1354792796%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1352868961&rft_id=info:pmid/23696902&rft_doaj_id=oai_doaj_org_article_3628d0ec52054786b9592425dae2f3f1&rfr_iscdi=true |