{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:31:56Z","timestamp":1790937116925,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2010,5,1]],"date-time":"2010-05-01T00:00:00Z","timestamp":1272672000000},"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":[[2010,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>TLR3 is one of the major innate immune sensors of dsRNA. The signal transduction pathway activated by TLR3, upon binding to dsRNA, leads to the activation of two major transcription factors: NF-\u03baB and IFN regulatory factor (IRF) 3. In an effort to identify specific chemical modulators of TLR3\u2013IRF3 signal transduction pathway, we developed a cell-based readout system. Using the IFN-stimulated gene 56 promoter-driven firefly luciferase gene stably integrated in a TLR3-expressing HEK293 cell line, we were able to generate a cell line where treatment with dsRNA resulted in a dose-dependent induction of luciferase activity. A screen of two pharmacologically active compound libraries using this system identified a number of TLR3\u2013IRF3 signaling pathway modulators. Among them we focused on a subset of inhibitors and characterized their mode of action. Several antipsychotic drugs, such as sertraline, trifluoperazine, and fluphenazine, were found to be direct inhibitors of the innate immune signaling pathway. These inhibitors also showed the ability to inhibit IFN-stimulated gene 56 induction mediated by TLR4 and TLR7\/8 pathways. Interestingly, they did not show significant effects on TLR3-, TLR7-, and TLR8-mediated NF-\u03baB activation. Detailed analysis of the signaling pathway indicated that these drugs might be exerting their inhibitory effects on IRF3 via PI3K signaling pathway. The data presented in this study provide mechanistic explanation of possible anti-inflammatory roles of some antipsychotic drugs.<\/jats:p>","DOI":"10.4049\/jimmunol.0903559","type":"journal-article","created":{"date-parts":[[2010,4,9]],"date-time":"2010-04-09T22:02:19Z","timestamp":1270850539000},"page":"5768-5776","source":"Crossref","is-referenced-by-count":62,"title":["High-Throughput Screening for TLR3\u2013IFN Regulatory Factor 3 Signaling Pathway Modulators Identifies Several Antipsychotic Drugs as TLR Inhibitors"],"prefix":"10.1093","volume":"184","author":[{"given":"Jianzhong","family":"Zhu","sequence":"first","affiliation":[{"name":"Molecular Virology Program, University of Pittsburgh Cancer Institute"},{"name":"Department of Microbiology and Molecular Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paishiun N","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Molecular Virology Program, University of Pittsburgh Cancer Institute"},{"name":"Department of Microbiology and Molecular Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne K","family":"Mburu","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Chattopadhyay","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganes C","family":"Sen","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saumendra N","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Molecular Virology Program, University of Pittsburgh Cancer Institute"},{"name":"Department of Microbiology and Molecular Genetics"},{"name":"Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,5,15]]},"reference":[{"key":"2026012806323399000_r1","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cell.2006.02.015","article-title":"Pathogen recognition and innate immunity.","volume":"124","author":"Akira","year":"2006","journal-title":"Cell"},{"key":"2026012806323399000_r2","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/35099560","article-title":"Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.","volume":"413","author":"Alexopoulou","year":"2001","journal-title":"Nature"},{"key":"2026012806323399000_r3","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature04734","article-title":"Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.","volume":"441","author":"Kato","year":"2006","journal-title":"Nature"},{"key":"2026012806323399000_r4","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/ni1087","article-title":"The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.","volume":"5","author":"Yoneyama","year":"2004","journal-title":"Nat. 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