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Because such cytokines as tumor necrosis factor (TNF)-\u03b1 and interferon-\u03b3 (IFN-\u03b3) have been shown to enhance RANTES induction in airway epithelial cells and RANTES gene expression appears to be differentially regulated depending on the cell type and the stimulus applied, in this study we have elucidated mechanisms that operate to control RANTES induction on exposure to TNF-\u03b1 and\/or IFN-\u03b3. Our results indicate that TNF-\u03b1 and IFN-\u03b3 synergistically induce RANTES protein secretion and mRNA expression. RANTES transcription is activated only after stimulation with TNF-\u03b1, but not IFN-\u03b3, which affects RANTES mRNA stabilization. Promoter deletion and mutagenesis experiments indicate that the nuclear factor (NF)-\u03baB site is the most important cis-regulatory element controlling TNF-induced RANTES transcription, although NF-interleukin-6 binding site, cAMP responsive element (CRE), and interferon-stimulated responsive element (ISRE) also play a significant role. TNF-\u03b1 stimulation induces nuclear translocation of interferon regulatory factor (IRF)-3, which in viral infection binds the RANTES ISRE and is necessary for activation of RANTES transcription. However, TNF-induced IRF-3 translocation does not result in IRF-3 binding to the RANTES ISRE. Although viral infection can activate an ISRE-driven promoter, TNF cannot, indicating that RANTES gene enhancers are controlled in a stimulus-specific fashion. Identification of molecular mechanisms involved in RANTES gene expression is fundamental for developing strategies to modulate lung inflammatory responses.<\/jats:p>","DOI":"10.1152\/ajplung.00162.2002","type":"journal-article","created":{"date-parts":[[2015,3,3]],"date-time":"2015-03-03T20:19:30Z","timestamp":1425413970000},"page":"L1280-L1290","source":"Crossref","is-referenced-by-count":49,"title":["Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation"],"prefix":"10.1152","volume":"283","author":[{"given":"Antonella","family":"Casola","sequence":"first","affiliation":[{"name":"Departments of Pediatrics,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allyne","family":"Henderson","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianshuang","family":"Liu","sequence":"additional","affiliation":[{"name":"Departments of 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