PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis
PKCε is implicated in T cell activation and proliferation and is overexpressed in CD4+‐T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune‐mediated disor...
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Veröffentlicht in: | European journal of immunology 2018-04, Vol.48 (4), p.644-654 |
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creator | Martini, Silvia Pozzi, Giulia Carubbi, Cecilia Masselli, Elena Galli, Daniela Di Nuzzo, Sergio Banchini, Antonio Gobbi, Giuliana Vitale, Marco Mirandola, Prisco |
description | PKCε is implicated in T cell activation and proliferation and is overexpressed in CD4+‐T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune‐mediated disorders is still largely unknown. We studied PKCε expression in circulating CD4+‐T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4+ subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCε is overexpressed in CD4+‐T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCε interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCε is forcibly downregulated, CD4+‐T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17‐lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCε as a potential target in Th17‐mediated diseases.
Under resting conditions, CD4+ T‐cells express low levels of PKCε. When stimulated with Th17‐promoting cytokines, PKCε is upregulated and induces Rorγt and IL17 expression, through phosphorylation of Stat3 at Ser727. This PKCε/Stat3 signaling pathway promotes the expansion of the CD4+Th17 cells, key players in the development of several immune‐mediated disorders. |
doi_str_mv | 10.1002/eji.201747102 |
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Under resting conditions, CD4+ T‐cells express low levels of PKCε. When stimulated with Th17‐promoting cytokines, PKCε is upregulated and induces Rorγt and IL17 expression, through phosphorylation of Stat3 at Ser727. This PKCε/Stat3 signaling pathway promotes the expansion of the CD4+Th17 cells, key players in the development of several immune‐mediated disorders.</description><identifier>ISSN: 0014-2980</identifier><identifier>EISSN: 1521-4141</identifier><identifier>DOI: 10.1002/eji.201747102</identifier><identifier>PMID: 29280140</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Adult ; Autoimmune diseases ; Autoimmunity ; Autoimmunity - immunology ; CD161 ; CD4 antigen ; Cell activation ; Cell Differentiation - immunology ; Cell Polarity - immunology ; Cell proliferation ; Cells, Cultured ; Female ; Hashimoto's thyroiditis ; Helper cells ; Humans ; Inflammation - immunology ; Inflammation - pathology ; Lymphocyte Activation - immunology ; Lymphocytes ; Lymphocytes T ; Male ; Middle Aged ; Molecular modelling ; Phototherapy ; Protein kinase C ; Protein Kinase C epsilon ; Protein Kinase C-epsilon - metabolism ; Psoriasis ; Psoriasis - immunology ; Psoriasis - physiopathology ; Skin ; Stat3 ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Th17 Cells - cytology ; Th17 Cells - immunology ; Thyroiditis</subject><ispartof>European journal of immunology, 2018-04, Vol.48 (4), p.644-654</ispartof><rights>2017 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4039-74b89cbaae66e459e4838c55616ba6cc781692fb32b1adbe0274287b68c80a3</citedby><cites>FETCH-LOGICAL-c4039-74b89cbaae66e459e4838c55616ba6cc781692fb32b1adbe0274287b68c80a3</cites><orcidid>0000-0001-5779-4292</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Feji.201747102$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Feji.201747102$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29280140$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martini, Silvia</creatorcontrib><creatorcontrib>Pozzi, Giulia</creatorcontrib><creatorcontrib>Carubbi, Cecilia</creatorcontrib><creatorcontrib>Masselli, Elena</creatorcontrib><creatorcontrib>Galli, Daniela</creatorcontrib><creatorcontrib>Di Nuzzo, Sergio</creatorcontrib><creatorcontrib>Banchini, Antonio</creatorcontrib><creatorcontrib>Gobbi, Giuliana</creatorcontrib><creatorcontrib>Vitale, Marco</creatorcontrib><creatorcontrib>Mirandola, Prisco</creatorcontrib><title>PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis</title><title>European journal of immunology</title><addtitle>Eur J Immunol</addtitle><description>PKCε is implicated in T cell activation and proliferation and is overexpressed in CD4+‐T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune‐mediated disorders is still largely unknown. We studied PKCε expression in circulating CD4+‐T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4+ subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCε is overexpressed in CD4+‐T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCε interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCε is forcibly downregulated, CD4+‐T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17‐lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCε as a potential target in Th17‐mediated diseases.
Under resting conditions, CD4+ T‐cells express low levels of PKCε. When stimulated with Th17‐promoting cytokines, PKCε is upregulated and induces Rorγt and IL17 expression, through phosphorylation of Stat3 at Ser727. This PKCε/Stat3 signaling pathway promotes the expansion of the CD4+Th17 cells, key players in the development of several immune‐mediated disorders.</description><subject>Adult</subject><subject>Autoimmune diseases</subject><subject>Autoimmunity</subject><subject>Autoimmunity - immunology</subject><subject>CD161</subject><subject>CD4 antigen</subject><subject>Cell activation</subject><subject>Cell Differentiation - immunology</subject><subject>Cell Polarity - immunology</subject><subject>Cell proliferation</subject><subject>Cells, Cultured</subject><subject>Female</subject><subject>Hashimoto's thyroiditis</subject><subject>Helper cells</subject><subject>Humans</subject><subject>Inflammation - immunology</subject><subject>Inflammation - pathology</subject><subject>Lymphocyte Activation - immunology</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Molecular modelling</subject><subject>Phototherapy</subject><subject>Protein kinase C</subject><subject>Protein Kinase C epsilon</subject><subject>Protein Kinase C-epsilon - metabolism</subject><subject>Psoriasis</subject><subject>Psoriasis - immunology</subject><subject>Psoriasis - physiopathology</subject><subject>Skin</subject><subject>Stat3</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Th17 Cells - cytology</subject><subject>Th17 Cells - immunology</subject><subject>Thyroiditis</subject><issn>0014-2980</issn><issn>1521-4141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90MFO3DAQBmCrKioL7bFXZKmXXgIzjhPb3NCKwgISlbrHSpbjdRqvkjjEiap9G16CF-gD8EyE7sKBAydr5E-_Zn5CviIcIwA7cWt_zAAFFwjsA5lhxjDhyPEjmQEgT5iSsE8OYlwDgMoz9YnsM8Xk9Acz8vvn9fzx4d9914cmDC7SamxMS5cVCrryZel61w7eDD60p3TRdLW3_4dIfUuHytHODFXoqk30oQ5_NjSUtIuh9yb6-JnslaaO7svuPSS_fpwv55fJze3FYn52k1gOqUoEL6SyhTEuzx3PlOMylTbLcswLk1srJOaKlUXKCjSrwgETnElR5NJKMOkh-b5NnW64G10cdOOjdXVtWhfGqFFJhIxzzCb67Q1dh7Fvp900A8alBAF8UslW2T7E2LtSd71vTL_RCPq5dD2Vrl9Ln_zRLnUsGrd61S8tT4BtwV9fu837afr8asFRqPQJnweNMg</recordid><startdate>201804</startdate><enddate>201804</enddate><creator>Martini, Silvia</creator><creator>Pozzi, Giulia</creator><creator>Carubbi, Cecilia</creator><creator>Masselli, Elena</creator><creator>Galli, Daniela</creator><creator>Di Nuzzo, Sergio</creator><creator>Banchini, Antonio</creator><creator>Gobbi, Giuliana</creator><creator>Vitale, Marco</creator><creator>Mirandola, Prisco</creator><general>Wiley Subscription Services, Inc</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>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5779-4292</orcidid></search><sort><creationdate>201804</creationdate><title>PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis</title><author>Martini, Silvia ; 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Although this might induce the suspicion that PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune‐mediated disorders is still largely unknown. We studied PKCε expression in circulating CD4+‐T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4+ subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCε is overexpressed in CD4+‐T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCε interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCε is forcibly downregulated, CD4+‐T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17‐lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCε as a potential target in Th17‐mediated diseases.
Under resting conditions, CD4+ T‐cells express low levels of PKCε. When stimulated with Th17‐promoting cytokines, PKCε is upregulated and induces Rorγt and IL17 expression, through phosphorylation of Stat3 at Ser727. This PKCε/Stat3 signaling pathway promotes the expansion of the CD4+Th17 cells, key players in the development of several immune‐mediated disorders.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>29280140</pmid><doi>10.1002/eji.201747102</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-5779-4292</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Adult Autoimmune diseases Autoimmunity Autoimmunity - immunology CD161 CD4 antigen Cell activation Cell Differentiation - immunology Cell Polarity - immunology Cell proliferation Cells, Cultured Female Hashimoto's thyroiditis Helper cells Humans Inflammation - immunology Inflammation - pathology Lymphocyte Activation - immunology Lymphocytes Lymphocytes T Male Middle Aged Molecular modelling Phototherapy Protein kinase C Protein Kinase C epsilon Protein Kinase C-epsilon - metabolism Psoriasis Psoriasis - immunology Psoriasis - physiopathology Skin Stat3 Stat3 protein STAT3 Transcription Factor - metabolism Th17 Cells - cytology Th17 Cells - immunology Thyroiditis |
title | PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis |
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