Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway

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Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators …"><meta name="keywords" content="pmid:18758466, PMC3732485, doi:10.1038/ni.1645, Research Support, N.I.H., Extramural, Weiping Cao, Santhakumar Manicassamy, Bali Pulendran, Animals, Dendritic Cells / drug effects, Dendritic Cells / immunology, Dendritic Cells / metabolism*, Electrophoresis, Polyacrylamide Gel, Flow Cytometry, Gene Expression Regulation / immunology, Humans, Immunoblotting, Immunosuppressive Agents / pharmacology, Interferon Type I / immunology, Interferon Type I / metabolism*, Mice, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Phosphatidylinositol 3-Kinases / immunology, Phosphatidylinositol 3-Kinases / metabolism, Protein Kinases / immunology, Protein Kinases / metabolism*, Ribosomal Protein S6 Kinases, 70-kDa / immunology, Ribosomal Protein S6 Kinases, 70-kDa / metabolism, Signal Transduction / immunology*, Sirolimus / pharmacology, TOR Serine-Threonine Kinases, Toll-Like Receptor 9 / immunology, Toll-Like Receptor 9 / metabolism*, Transfection, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/18758466/"><meta property="og:description" content="Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/18758466/"><meta name="twitter:description" content="Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">  <link rel="search" type="application/opensearchdescription+xml" href="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/opensearch.xml" title="PubMed search">  <noscript> <link rel="stylesheet" type="text/css" href="https://cdn.ncbi.nlm.nih.gov/pubmed/ed1a5a1f-b279-475e-88e3-75f261729818/core/no-script.css"> </noscript> <meta name="citation_title" content="Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway"> <meta name="citation_authors" content="Cao W;Manicassamy S;Tang H;Kasturi SP;Pirani A;Murthy N;Pulendran B;"> <meta name="citation_date" content="2008 Oct"> <meta name="citation_publisher" content="Nat Immunol"> <meta name="citation_journal_title" content="Nature immunology"> <meta name="citation_pmid" content="18758466"> <meta name="citation_abstract_html_url" content="https://pubmed.ncbi.nlm.nih.gov/18758466/"> <meta name="citation_volume" content="9"> <meta name="citation_issue" content="10"> <meta name="citation_doi" content="10.1038/ni.1645"> <meta name="citation_issn" content="1529-2916"> <link rel="canonical" href="https://pubmed.ncbi.nlm.nih.gov/18758466/" /> </head> <body > <noscript> <div class="no-script-banner" id="no-script-banner"> <div class="warning-message"> <div class="warning-message-text"> This site needs JavaScript to work properly. 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new collection</label> </li> <li> <input type="radio" id="collections-action-panel-existing" class="collections-existing" name="collections" value="existing" checked="true" data-ga-category="save_share" data-ga-action="collections" data-ga-label="collections_radio_existing"> <label for="collections-action-panel-existing">Add to an existing collection</label> </li> </ul> </div> <div class="controls-wrapper"> <div class="action-panel-control-wrap new-collections-controls"> <label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk"> Name your collection: </label> <input type="text" name="add-to-new-collection" id="collections-action-panel-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="save_share" data-ga-action="create_collection" data-ga-label="non_favorties_collection"> <div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="Spzqiz91wiOLaIe2WQE63pE8UJlIBk4XNhzLQ0TEVpLPWGYUspTKWMWcEQ2gFwHV"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="Spzqiz91wiOLaIe2WQE63pE8UJlIBk4XNhzLQ0TEVpLPWGYUspTKWMWcEQ2gFwHV"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="Spzqiz91wiOLaIe2WQE63pE8UJlIBk4XNhzLQ0TEVpLPWGYUspTKWMWcEQ2gFwHV"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="Spzqiz91wiOLaIe2WQE63pE8UJlIBk4XNhzLQ0TEVpLPWGYUspTKWMWcEQ2gFwHV"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="18758466"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button><button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" 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ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Santhakumar Manicassamy">Santhakumar Manicassamy</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Tang+H&cauthor_id=18758466" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Hua Tang">Hua Tang</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kasturi+SP&cauthor_id=18758466" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Sudhir Pai Kasturi">Sudhir Pai Kasturi</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Pirani+A&cauthor_id=18758466" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Ali Pirani">Ali Pirani</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Murthy+N&cauthor_id=18758466" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Niren Murthy">Niren Murthy</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Pulendran+B&cauthor_id=18758466" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Bali Pulendran">Bali Pulendran</a></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliation </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Emory Vaccine Center, Atlanta, GA 30329, USA.</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">18758466</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC3732485&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3732485/" data-ga-category="full_text" data-ga-action="PMCID" > PMC3732485 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.1038/ni.1645&id_type=DOI" href="https://doi.org/10.1038/ni.1645" data-ga-category="full_text" data-ga-action="DOI" > 10.1038/ni.1645 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> </div> </header> <div class="actions-buttons inline"><div class="inner-wrap"><button class="full-text-links-button full-text-links-dialog-trigger" title="Open dialog with full text links" ref="linksrc=full_text_links"> Full text links </button><button class="citation-button citation-dialog-trigger" aria-label="Open dialog with citation text in different styles" data-ga-category="save_share" data-ga-action="cite" data-ga-label="open" data-all-citations-url="/18758466/citations/" data-citation-style="nlm" data-pubmed-format-link="/18758466/export/"><span class="button-label">Cite</span></button><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format" data-default-format-value="abstract" data-current-format-value="abstract" role="region"><button class="trigger usa-button" title="Change format" data-ga-category="display_options" data-ga-action="display_options_dialog"><span class="button-label">Display options</span></button><div class="dropdown" hidden><div class="title"> Display options </div><div class="content"><div class="format-container"><span class="option-label"> Format </span><select name="format" data-initial-value="abstract" aria-label="Display format" id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-alpha/beta production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-alpha/beta production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-alpha/beta responses by pDCs. </p> </div> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" ga_category="literature_resources" ga_action="disclaimer_link" ga_label="under_abstract">PubMed Disclaimer</a> </p> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="figure-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/8616e3ecd533/nihms494939f1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="603" data-image-height="397" data-image-alt="Figure 1" data-pmc-id="PMC3732485" data-figure-id="F1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/edf26ec544af/nihms494939f1.gif" alt="Figure 1" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="603"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="397"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1 </p> </strong> <div class="figure-caption-contents"><p> Rapamycin inhibits TLR-mediated IFN-α secretion… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1 </p> </strong> <div class="figure-caption-contents"><p> Rapamycin inhibits TLR-mediated IFN-α secretion by pDCs. ( <b> a </b> ) ELISA of IFN-α… </p></div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1 </strong> <div class="figure-caption-contents">Rapamycin inhibits TLR-mediated IFN-α secretion by pDCs. (<b>a</b>) ELISA of IFN-α in supernatants of isolated pDCs pretreated for 3 h with various doses of rapamycin (Rap) and then stimulated with CpG-A (10 μg/ml; left) or treated with vehicle (Veh) or rapamycin and then stimulated with various doses of CpG-A (right). (<b>b</b>) ELISA of IFN-β, TNF, IL-6 and CXCL10 in supernatants of purified mouse pDCs pretreated with various doses of rapamycin and then stimulated for 24 h with CpG-A (10 μg/ml). (<b>c</b>) ELISA of IFN-α in supernatants of purified spleen pDCs cultured for 24 h with CpG-A (10 μg/ml), loxoribine (Loxo; 1 mM), YF-17D or vesicular stomatitis virus (VSV; all viruses at a multiplicity of infection of 1) after pretreatment with rapamycin (Rap) or vehicle. (<b>d</b>) Apoptotic death of isolated mouse pDCs pretreated with vehicle or 20 nM or 500 nM rapamycin, assessed by staining with annexin V and propidium iodide. Numbers in quadrants indicate percent cells in each. (<b>e</b>) Proliferation of and cytokine induction in naive CD4<sup>+</sup>CD62L<sup>+</sup> OT-II T cells (1 × 10<sup>5</sup> cells/ well) cultured with pDCs (5 × 10<sup>4</sup>) pretreated with ovalbumin peptide (10 μg/ml) and CpG-A (10 μg/ml) plus vehicle or rapamycin (100 nM for 3 h), assessed after 3 d by incorporation of [<sup>3</sup>H]thymidine (top left; proliferation) and ELISA of IFN-γ, IL-4, IL-10, IL-13 and IL-17. *, <i>P</i> < 0.05; **, <i>P</i> < 0.001; ***, <i>P</i> < 0.0001. Data are representative of at least three independent experiments (error bars, s.d.).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="figure-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/e505d663ebf5/nihms494939f2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="729" data-image-height="769" data-image-alt="Figure 2" data-pmc-id="PMC3732485" data-figure-id="F2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/650d2a87d9b9/nihms494939f2.gif" alt="Figure 2" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="729"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="769"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2 </p> </strong> <div class="figure-caption-contents"><p> Expression of rapamycin-sensitive mTOR pathway… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2 </p> </strong> <div class="figure-caption-contents"><p> Expression of rapamycin-sensitive mTOR pathway components in pDCs. ( <b> a </b> ) Immunoblot analysis… </p></div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2 </strong> <div class="figure-caption-contents">Expression of rapamycin-sensitive mTOR pathway components in pDCs. (<b>a</b>) Immunoblot analysis of phosphorylated (phospho-) and total mTOR in lysates of RAW cells (4 × 10<sup>6</sup>) transiently transfected for 40 h with cyan fluorescent protein–tagged MyD88 and IRF7-YFP, treated with vehicle (−) or rapamycin (+) and then stimulated for 0–60 min with CpG-A–DOTAP. Results are representative of two independent experiments. (<b>b</b>) Immunoblot analysis of phosphorylated and total mTOR, p70S6K, 4E-BP1 and Akt in lysates of purified pDCs (1 × 10<sup>6</sup>) stimulated for 15 min with CpG-A in the presence (Rap) or absence (Medium) of rapamycin. Results are representative of three independent experiments.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="figure-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/81d0815bcef7/nihms494939f3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="685" data-image-height="591" data-image-alt="Figure 3" data-pmc-id="PMC3732485" data-figure-id="F3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/78450ba91d0a/nihms494939f3.gif" alt="Figure 3" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="685"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="591"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3 </p> </strong> <div class="figure-caption-contents"><p> TLR-mediated induction of IFN-α in… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3 </p> </strong> <div class="figure-caption-contents"><p> TLR-mediated induction of IFN-α in pDCs depends on the mTOR signaling pathway. (… </p></div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3 </strong> <div class="figure-caption-contents">TLR-mediated induction of IFN-α in pDCs depends on the mTOR signaling pathway. (<b>a</b>) ELISA of IFN-α in supernatants (above) and immunoblot analysis of mTOR in lysates (below) of purified mouse pDCs (5 × 10<sup>5</sup>) transfected for 5 h with control or mTOR-specific siRNA and then stimulated for 24 h with CpG-A. Below, β-actin serves as a loading control. (<b>b</b>) ELISA of IFN-α in supernatants of pDCs treated with rapamycin or the PI(3)K inhibitor LY294002 (1–25 μM), then stimulated with CpG-A and assessed 24 h later. (<b>c</b>) ELISA of IFN-α in supernatants (above) and immunoblot analysis of p70S6K in lysates (below) of mouse pDCs transfected for 5 h with siRNA pools specific for p70S6K1 (S6K1), p70S6K2 (S6K2) or both (S6K1,2), then stimulated for 24 h with CpG-A. *, <i>P</i> < 0.05. (<b>d</b>) ELISA of IFN-α in supernatants of pDCs isolated from wild-type (WT) and <i>Rps6k1</i><sup>−/−</sup><i>Rps6k2</i><sup>−/−</sup> double-knockout (S6K1,2-KO) mouse spleens and stimulated <i>in vitro</i> with CpG-A. Data are representative of three independent experiments (<b>a–c</b>) or two independent experiments with at least two mice per group per experiment (<b>d</b>); error bars, s.e.m. of replicate wells.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="figure-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/dd67af69d3ed/nihms494939f4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="795" data-image-height="492" data-image-alt="Figure 4" data-pmc-id="PMC3732485" data-figure-id="F4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/a68e67871d79/nihms494939f4.gif" alt="Figure 4" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="795"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="492"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4 </p> </strong> <div class="figure-caption-contents"><p> Rapamycin does not affect TLR9… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4 </p> </strong> <div class="figure-caption-contents"><p> Rapamycin does not affect TLR9 expression or interaction with CpG-A. ( <b> a </b> )… </p></div> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4 </strong> <div class="figure-caption-contents">Rapamycin does not affect TLR9 expression or interaction with CpG-A. (<b>a</b>) Flow cytometry of isolated spleen pDCs stimulated with CpG-A with or without rapamycin pretreatment, then stained for intracellular TLR9. (<b>b</b>) Deconvolution microscopy of RAW cells expressing YFP-tagged TLR9 (green), pretreated with vehicle (left) or rapamycin (right) and then incubated for 90 min with indodicarbocyanine-tagged CpG-A–DOTAP (red; 5 μg/ml). Two images were obtained for each condition. Data are representative of two independent experiments.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="figure-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/903256d8e19b/nihms494939f5.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="704" data-image-height="412" data-image-alt="Figure 5" data-pmc-id="PMC3732485" data-figure-id="F5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/97842becaec0/nihms494939f5.gif" alt="Figure 5" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="704"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="412"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5 </p> </strong> <div class="figure-caption-contents"><p> Rapamycin inhibits the spatial interaction… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5 </p> </strong> <div class="figure-caption-contents"><p> Rapamycin inhibits the spatial interaction of TLR9 with the MyD88-IRF7 complex and affects… </p></div> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5 </strong> <div class="figure-caption-contents">Rapamycin inhibits the spatial interaction of TLR9 with the MyD88-IRF7 complex and affects the phosphorylation and nuclear translocation of IRF7. (<b>a</b>) Immunoassay of RAW cells (4 × 10<sup>6</sup>) transfected with hemagglutinin-tagged MyD88 and YFP-tagged TLR9 and then, 36 h later, stimulated for 90 min with CpG-A–DOTAP; cell extracts were immunoprecipitated (IP) with anti-hemagglutinin and analyzed by immunoblot (IB) for coprecipitated TLR9. MyD88 serves as a loading control. (<b>b</b>) Flow cytometry of human pDCs pretreated with rapamycin (left) or transfected with control (con) siRNA or siRNA specific for p70S6K1 and p70S6K2 (S6K), then stimulated for 45 min with CpG-A; cells were fixed, made permeable and stained with phycoerythrin-conjugated mouse antibody to IRF7 phosphorylated at Ser477 and Ser479 (phosphor-IRF7) or control isotype antibody (Control Ab; phycoerythrin-conjugated mouse immunoglobulin G1). (<b>c</b>) Confocal microscopy of purified mouse pDCs stimulated for 12 h with CpG-A in the presence of rapamycin or vehicle, then fixed with formaldehyde, made permeable with saponin, blocked with 20% (vol/vol) goat serum, stained with anti-IRF7 (green) and mounted with ProLong Gold antifade reagent with DAPI (blue). Scale bar, 2 μm. (<b>d</b>) Luciferase assay of HEK293 cells transiently transfected with 0 ng (−), 40 ng or 200 ng of constitutively active IRF7 (IRF7-D477,479) together with luciferase-tagged IFN-β (plasmid p125-Luc; 50 ng), renilla luciferase (0.5 ng), wild-type IRF7 (3 ng), MyD88 (20 ng) and TLR9 (50 ng), cultured for 24 h, then pretreated for 3 h with 100 nM rapamycin and then stimulated overnight with CpG-A (10 μg/ml). Empty vector, vector without IRF7. Data are representative of three (<b>a</b>,<b>d</b>) or two (<b>b</b>,<b>c</b>) independent experiments (error bars (<b>d</b>), s.d.).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="5" data-label-slug="figure-6"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/a899d506669a/nihms494939f6.jpg" itemprop="contentUrl" aria-describedby="figure-caption-5" role="button" data-image-width="800" data-image-height="519" data-image-alt="Figure 6" data-pmc-id="PMC3732485" data-figure-id="F6"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-5" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/d8c424444659/nihms494939f6.gif" alt="Figure 6" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="800"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="519"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 6 </p> </strong> <div class="figure-caption-contents"><i> In vivo </i> administration of rapamycin…</div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 6 </p> </strong> <div class="figure-caption-contents"><i> In vivo </i> administration of rapamycin inhibits YF-17D-induced production of IFN-α in the serum.…</div> </div> <figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 6 </strong> <div class="figure-caption-contents"><i>In vivo</i> administration of rapamycin inhibits YF-17D-induced production of IFN-α in the serum. (<b>a</b>) ELISA of IFN-α production by pDCs from C57BL/6 mice treated daily for 3 d with soluble rapamycin (1.5 mg per kg body weight per day) or rapamycin encapsulated in PLGA microparticles (2 mg per mouse per day), then vaccinated subcutaneously with YF-17D on day 4; blood and spleens were obtained at various times after injection for analysis of serum (right) and pDCs enriched from spleens with microbeads coated with anti–mouse PDCA1 (left). *<i>P</i> < 0.05; **<i>P</i> < 0.001; ***<i>P</i> < 0.0001. Data are representative of at least three independent experiments (error bars, s.d.). (<b>b</b>) Flow cytometry of ovalbumin (OVA) in cells from C57BL/6 mice left untreated (top row) or subcutaneously injected with Alexa Fluor 488–labeled ovalbumin encapsulated in PLGA microparticles (bottom row); draining lymph nodes were isolated 24 h later and treated for 30 min at 37 °C with collagenase type IV, then isolated cells were stained for cell surface lineage markers to identify cell type (above plots). Numbers below outlined areas indicate percent cells containing OVA. cDCs, conventional DCs. Data are representative of three independent experiments.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="6" data-label-slug="figure-7"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/205b9a06ed52/nihms494939f7.jpg" itemprop="contentUrl" aria-describedby="figure-caption-6" role="button" data-image-width="800" data-image-height="456" data-image-alt="Figure 7" data-pmc-id="PMC3732485" data-figure-id="F7"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-6" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bee3/3732485/7ec02c538e73/nihms494939f7.gif" alt="Figure 7" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="800"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="456"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 7 </p> </strong> <div class="figure-caption-contents"><p> Inhibition of mTOR in APCs… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 7 </p> </strong> <div class="figure-caption-contents"><p> Inhibition of mTOR in APCs <i> in vivo </i> can suppress the adaptive immune response… </p></div> </div> <figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 7 </strong> <div class="figure-caption-contents">Inhibition of mTOR in APCs <i>in vivo</i> can suppress the adaptive immune response to a vaccine. IFN-γ production (top right) and cytokine expression (top left and bottom) by CD8<sup>+</sup> T cells enriched from draining lymph nodes of C57BL/6 mice left untreated (−) or treated daily for 3 d with vehicle or rapamycin microparticles (2 mg per mouse per day) and then vaccinated subcutaneously on day 4 with YF-17D; 5 d later, single-cell suspensions were cultured for an additional 3 d <i>in vitro</i> in medium alone (left bars) or with a CD8<sup>+</sup> T cell epitope from YF-17D (middle and right bars). IFN-γ was assessed by intracellular cytokine staining and flow cytometry; numbers above outlined areas indicate percent CD8<sup>+</sup>IFN-γ<sup>+</sup> cells. IFN-γ, IL-4, IL-13, IL-10 and IL-17 in cell supernatants were measured by ELISA. *, <i>P</i> < 0.05. Data are representative of three independent experiments (error bars, s.d.).</div> </figcaption> </figure> </div> <div class="see-all actions-bar"> <button class="show-more" aria-controls="slides-container" data-ga-category="figure" data-ga-action="show_all"> All figures (7) </button> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button class="pswp__button pswp__button--share" title="Share"></button> <button class="pswp__button pswp__button--fs" title="Toggle fullscreen"></button> <button class="pswp__button pswp__button--zoom" title="Zoom in/out"></button>   <div class="pswp__preloader"> <div class="pswp__preloader__icn"> <div class="pswp__preloader__cut"> <div class="pswp__preloader__donut"></div> </div> </div> </div> </div> <div class="pswp__share-modal pswp__share-modal--hidden pswp__single-tap"> <div class="pswp__share-tooltip"></div> </div> <button class="pswp__button pswp__button--arrow--left" title="Previous (arrow left)"> </button> <button class="pswp__button pswp__button--arrow--right" title="Next (arrow right)"> </button> <div class="pswp__caption"> <div class="pswp__caption__center"></div> </div> </div> </div> </div> <div class="figure-dialog-caption"> <div class="figure-caption-link-container"> <a class="figure-caption-link" href="#">See this image and copyright information in PMC</a> </div> <div class="figure-caption-center" data-expand-title="click to show full caption" data-collapse-title="click to hide full caption"> </div> <button class="figure-caption-toggle-btn" aria-label="show full caption" data-expand-text="show full caption" data-collapse-text="hide full caption">  </button> </div> </div> <div class="similar-articles" id="similar"> <h2 class="title"> Similar articles </h2> <ul class="articles-list" id="similar-articles-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/12759354/" ref="article_id=12759354&linksrc=similar_articles_link&ordinalpos=1" data-ga-category="similar_article" data-ga-action="12759354" data-ga-label=""> Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Lekmine F, Uddin S, Sassano A, Parmar S, Brachmann SM, Majchrzak B, Sonenberg N, Hay N, Fish EN, Platanias LC.</span> <span class="docsum-authors short-authors">Lekmine F, et al.</span> <span class="docsum-journal-citation full-journal-citation">J Biol Chem. 2003 Jul 25;278(30):27772-80. doi: 10.1074/jbc.M301364200. 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Signal Transduction / immunology*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-21" aria-expanded="false" data-pinger-ignore> Signal Transduction / immunology* </button><div id="keyword-actions-mesh-terms-major-21" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Signal Transduction / immunology*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Signal+Transduction%2Fimmunology%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Signal+Transduction%2Fimmunology%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Signal Transduction/immunology"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Signal Transduction / immunology*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" 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Receptor 9 / immunology" tabindex="0" aria-controls="keyword-actions-mesh-terms-24" aria-expanded="false" data-pinger-ignore> Toll-Like Receptor 9 / immunology </button><div id="keyword-actions-mesh-terms-24" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Toll-Like Receptor 9 / immunology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Toll-Like+Receptor+9%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Toll-Like+Receptor+9%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Toll-Like Receptor 9/immunology"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Toll-Like Receptor 9 / immunology"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" 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dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Immunosuppressive Agents" tabindex="0" aria-controls="keyword-actions-substances-0" aria-expanded="false" data-pinger-ignore> Immunosuppressive Agents </button><div id="keyword-actions-substances-0" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Immunosuppressive Agents"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Immunosuppressive+Agents%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Immunosuppressive+Agents%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="Immunosuppressive Agents"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="Immunosuppressive Agents"> Search in PubMed </a></li><li><a class="search-in-mesh-link 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Receptor 9 </button><div id="keyword-actions-substances-3" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Toll-Like Receptor 9"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Toll-Like+Receptor+9%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Toll-Like+Receptor+9%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="Toll-Like Receptor 9"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="Toll-Like Receptor 9"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=%22Toll-Like+Receptor+9%22" data-ga-category="search_mesh" data-ga-action="substance_link" data-ga-label="Toll-Like Receptor 9"> Search in MeSH </a></li><li><a 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protein, human" tabindex="0" aria-controls="keyword-actions-substances-5" aria-expanded="false" data-pinger-ignore> MTOR protein, human </button><div id="keyword-actions-substances-5" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword MTOR protein, human"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22MTOR+protein%2C+human%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22MTOR+protein%2C+human%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="MTOR protein, human"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="MTOR protein, human"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=%22MTOR+protein%2C+human%22" data-ga-category="search_mesh" 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Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway - PubMed