title: Tumor-produced, active interleukin-1β regulates gene expression in carcinoma-associated fibroblasts.
abstract: Recently we described a co-culture model of periodontal ligament (PDL) fibroblasts and SCC-25 lingual squamous carcinoma cells, which resulted in conversion of normal fibroblasts into carcinoma-associated fibroblasts (CAFs), and in epithelial-mesenchymal transition (EMT) of SCC-25 cells. We have found a constitutive high interleukin-1β (IL1-β) expression in SCC-25 cells in normal and in co-cultured conditions. In our hypothesis a constitutive IL1-β expression in SCC-25 regulates gene expression in fibroblasts during co-culture. Co-cultures were performed between PDL fibroblasts and SCC-25 cells with and without dexamethasone (DEX) treatment; IL1-β processing was investigated in SCC-25 cells, tumor cells and PDL fibroblasts were treated with IL1-β. IL1-β signaling was investigated by western blot and immunocytochemistry. IL1-β-regulated genes were analyzed by real-time qPCR. SCC-25 cells produced 16kD active IL1-β, its receptor was upregulated in PDL fibroblasts during co-culture, which induced phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1), and nuclear translocalization of NFκBα. Several genes, including interferon regulatory factor 1 (IRF1) interleukin-6 (IL-6) and prostaglandin-endoperoxide synthase 2 (COX-2) were induced in CAFs during co-culture. The most enhanced induction was found for IL-6 and COX-2. Treatment of PDL fibroblasts with IL1-β reproduced a time- and dose-dependent upregulation of IL1-receptor, IL-6 and COX-2. A further proof was achieved by DEX inhibition for IL1-β-stimulated IL-6 and COX-2 gene expression. Constitutive expression of IL1-β in the tumor cells leads to IL1-β-stimulated gene expression changes in tumor-associated fibroblasts, which are involved in tumor progression.
authors.affiliation: Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, Innsbruck, Austria. Jozsef.Dudas@i-med.ac.at
authors.forename: József
authors.initials: J
authors.lastname: Dudás
authors.forename: Alexandra
authors.initials: A
authors.lastname: Fullár
authors.forename: Mario
authors.initials: M
authors.lastname: Bitsche
authors.forename: Volker
authors.initials: V
authors.lastname: Schartinger
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.forename: Georg Mathias
authors.initials: GM
authors.lastname: Sprinzl
authors.forename: Herbert
authors.initials: H
authors.lastname: Riechelmann
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human