{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:47:12Z","timestamp":1789386432132,"version":"build-2803163510"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor\u2013induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b+ conventional DCs (cDCs), CD8+ cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow\u2013derived DCs (BMDCs) displayed enhanced production of TNF-\u03b1, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP\u2013deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP+\/\u2212 macrophages. Additionally, the increased activation in c-FLIP\u2013deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1402944","type":"journal-article","created":{"date-parts":[[2015,8,4]],"date-time":"2015-08-04T01:50:15Z","timestamp":1438653015000},"page":"2612-2623","source":"Crossref","is-referenced-by-count":20,"title":["Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling"],"prefix":"10.1093","volume":"195","author":[{"given":"Yu-Jung","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Immunology, National Taiwan University , Taipei 10051, Taiwan ,","place":["Republic of China"]},{"name":"Institute of Molecular Biology, Academia Sinica , Taipei 11529, Taiwan ,","place":["Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Hsuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, Academia Sinica , Taipei 11529, Taiwan ,","place":["Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Ting","family":"Mo","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, Academia Sinica , Taipei 11529, Taiwan ,","place":["Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huey-Wen","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, Academia Sinica , Taipei 11529, Taiwan ,","place":["Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Wen","family":"He","sequence":"additional","affiliation":[{"name":"Department of Immunology, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3237-4803","authenticated-orcid":false,"given":"Ming-Zong","family":"Lai","sequence":"additional","affiliation":[{"name":"Institute of Immunology, National Taiwan University , Taipei 10051, Taiwan ,","place":["Republic of China"]},{"name":"Institute of Molecular Biology, Academia Sinica , Taipei 11529, Taiwan ,","place":["Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,9,15]]},"reference":[{"key":"2025030704133440100_r1","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/nri1787","article-title":"cFLIP regulation of lymphocyte activation and development","volume":"6","author":"Budd","year":"2006","journal-title":"Nat. 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