TLR4 as a negative regulator of keratinocyte proliferation
TLR4 is an innate immune receptor with expression in human skin, keratinocytes as well as squamous cell carcinoma (SCC) of the skin. In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with...
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| creator | Iotzova-Weiss, Guergana Freiberger, Sandra N Johansen, Pål Kamarachev, Jivko Guenova, Emmanuella Dziunycz, Piotr J Roux, Guillaume A Neu, Johannes Hofbauer, Günther F L |
| description | TLR4 is an innate immune receptor with expression in human skin, keratinocytes as well as squamous cell carcinoma (SCC) of the skin. In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1 and TFPI. In summary, TLR4 negatively regulates the proliferation of keratinocytes and its overexpression reduces tumor growth of SCC cells. |
| doi_str_mv | 10.1371/journal.pone.0185668 |
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In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1 and TFPI. In summary, TLR4 negatively regulates the proliferation of keratinocytes and its overexpression reduces tumor growth of SCC cells.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0185668</identifier><identifier>PMID: 28982115</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activating transcription factor 3 ; Activating Transcription Factor 3 - metabolism ; Animals ; Biochemistry ; Biology ; Biology and Life Sciences ; Biopsy ; Calcium ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - pathology ; Cell cycle ; Cell Line ; Cell migration ; Cell proliferation ; Cell Proliferation - physiology ; Dermatology ; Down-regulation ; Gene expression ; Gene Knockdown Techniques ; Genetic aspects ; Humans ; Interferon Regulatory Factors - metabolism ; Interleukin 6 ; JNK protein ; Keratinocytes ; Keratinocytes - cytology ; Medical research ; Medicine and Health Sciences ; Melanoma ; Metastasis ; Mice ; Mice, Nude ; Pathology ; Phosphorylation ; Psoriasis ; Research and Analysis Methods ; Skin ; Skin cancer ; Skin diseases ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; Squamous cell carcinoma ; TLR4 ; TLR4 protein ; Toll-Like Receptor 4 - genetics ; Toll-Like Receptor 4 - physiology ; Toll-like receptors ; Transcription factors ; Tumor cells ; Tumors</subject><ispartof>PloS one, 2017-10, Vol.12 (10), p.e0185668-e0185668</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Iotzova-Weiss 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. 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In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1 and TFPI. 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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>Iotzova-Weiss, Guergana</au><au>Freiberger, Sandra N</au><au>Johansen, Pål</au><au>Kamarachev, Jivko</au><au>Guenova, Emmanuella</au><au>Dziunycz, Piotr J</au><au>Roux, Guillaume A</au><au>Neu, Johannes</au><au>Hofbauer, Günther F L</au><au>Brandner, Johanna M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TLR4 as a negative regulator of keratinocyte proliferation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-10-05</date><risdate>2017</risdate><volume>12</volume><issue>10</issue><spage>e0185668</spage><epage>e0185668</epage><pages>e0185668-e0185668</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>TLR4 is an innate immune receptor with expression in human skin, keratinocytes as well as squamous cell carcinoma (SCC) of the skin. In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1 and TFPI. In summary, TLR4 negatively regulates the proliferation of keratinocytes and its overexpression reduces tumor growth of SCC cells.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28982115</pmid><doi>10.1371/journal.pone.0185668</doi><tpages>e0185668</tpages><orcidid>https://orcid.org/0000-0002-7033-9507</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activating transcription factor 3 Activating Transcription Factor 3 - metabolism Animals Biochemistry Biology Biology and Life Sciences Biopsy Calcium Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Cell cycle Cell Line Cell migration Cell proliferation Cell Proliferation - physiology Dermatology Down-regulation Gene expression Gene Knockdown Techniques Genetic aspects Humans Interferon Regulatory Factors - metabolism Interleukin 6 JNK protein Keratinocytes Keratinocytes - cytology Medical research Medicine and Health Sciences Melanoma Metastasis Mice Mice, Nude Pathology Phosphorylation Psoriasis Research and Analysis Methods Skin Skin cancer Skin diseases Skin Neoplasms - metabolism Skin Neoplasms - pathology Squamous cell carcinoma TLR4 TLR4 protein Toll-Like Receptor 4 - genetics Toll-Like Receptor 4 - physiology Toll-like receptors Transcription factors Tumor cells Tumors |
| title | TLR4 as a negative regulator of keratinocyte proliferation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T14%3A34%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TLR4%20as%20a%20negative%20regulator%20of%20keratinocyte%20proliferation&rft.jtitle=PloS%20one&rft.au=Iotzova-Weiss,%20Guergana&rft.date=2017-10-05&rft.volume=12&rft.issue=10&rft.spage=e0185668&rft.epage=e0185668&rft.pages=e0185668-e0185668&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0185668&rft_dat=%3Cgale_plos_%3EA508208941%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1991851095&rft_id=info:pmid/28982115&rft_galeid=A508208941&rft_doaj_id=oai_doaj_org_article_47e86f4dd20c4a238870dfc7fd49be8c&rfr_iscdi=true |