{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:20:36Z","timestamp":1791264036526,"version":"4.1.0"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2004,5,1]],"date-time":"2004-05-01T00:00:00Z","timestamp":1083369600000},"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":[[2004,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We recently proposed that Th1 and Th2 cytokines exert opposite effects on the pathogenesis and clinical outcome of organ-specific autoimmunity by altering the expression of genes involved in target cell survival. Because a Th2 response against tumors is associated with poor prognosis, we investigated the ability of IL-4 to protect tumor cells from death receptor- and chemotherapy-induced apoptosis. We found that IL-4 treatment significantly reduced CD95 (Fas\/APO-1)- and chemotherapeutic drug-induced apoptosis in prostate, breast, and bladder tumor cell lines. Analysis of antiapoptotic protein expression revealed that IL-4 stimulation resulted in up-regulation of cellular (c) FLIP\/FLAME-1 and Bcl-xL. Exogenous expression of cFLIP\/FLAME-1 inhibited apoptosis induced by CD95 and to a lesser extent by chemotherapy, while tumor cells transduced with Bcl-xL were substantially protected both from CD95 and chemotherapeutic drug stimulation. Moreover, consistent IL-4 production and high expression of both cFLIP\/FLAME-1 and Bcl-xL were observed in primary prostate, breast, and bladder cancer in vivo. Finally, primary breast cancer cells acquired sensitivity to apoptosis in vitro only in the absence of IL-4. Thus, IL-4 protects tumor cells from CD95- and chemotherapy-induced apoptosis through the up-regulation of antiapoptotic proteins such as cFLIP\/FLAME-1 and Bcl-xL. These findings may provide useful information for the development of therapeutic strategies aimed at restoring the functionality of apoptotic pathways in tumor cells.<\/jats:p>","DOI":"10.4049\/jimmunol.172.9.5467","type":"journal-article","created":{"date-parts":[[2014,4,20]],"date-time":"2014-04-20T20:08:23Z","timestamp":1398024503000},"page":"5467-5477","source":"Crossref","is-referenced-by-count":140,"title":["IL-4 Protects Tumor Cells from Anti-CD95 and Chemotherapeutic Agents via Up-Regulation of Antiapoptotic Proteins"],"prefix":"10.1093","volume":"172","author":[{"given":"Concetta","family":"Conticello","sequence":"first","affiliation":[{"name":"Department of Experimental Oncology, Mediterranean Institute of Oncology , Catania ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pedini","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Istituto Superiore di Sanita\u0300 , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Zeuner","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Mediterranean Institute of Oncology , Catania ,","place":["Italy"]},{"name":"Department of Hematology and Oncology, Istituto Superiore di Sanita\u0300 , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariella","family":"Patti","sequence":"additional","affiliation":[{"name":"Department of Surgical and Oncological Sciences, University of Palermo , Palermo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Zerilli","sequence":"additional","affiliation":[{"name":"Department of Surgical and Oncological Sciences, University of Palermo , Palermo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Stassi","sequence":"additional","affiliation":[{"name":"Department of Surgical and Oncological Sciences, University of Palermo , Palermo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Messina","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, General Pathology Section, University of Catania , Catania ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Peschle","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Istituto Superiore di Sanita\u0300 , Rome ,","place":["Italy"]},{"name":"Kimmel Cancer Center, Thomas Jefferson University , Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruggero","family":"De Maria","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Mediterranean Institute of Oncology , Catania ,","place":["Italy"]},{"name":"Department of Hematology and Oncology, Istituto Superiore di Sanita\u0300 , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2004,5,1]]},"reference":[{"key":"2026020211293271800_R1","first-page":"4301","volume-title":"Cancer Res.","year":"2001"},{"key":"2026020211293271800_R2","first-page":"63","volume-title":"Mol. 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