title: Toll-like receptor agonists induce inflammation and cell death in a model of head and neck squamous cell carcinomas.
abstract: Toll-like receptors (TLRs) are increasingly implicated in the pathogenesis of cancer. The present study describes TLR expression and function in healthy and malignant airway epithelial cells. The squamous cell carcinoma cell line Detroit-562 was compared with the healthy bronchial epithelial cell line NL-20 and primary human nasal epithelial cells (HNECs). TLR2, TLR3 and TLR5 were present in primary head and neck squamous cell carcinomas (HNSCCs). Consistent with this, Detroit-562 expressed TLR2, TLR3 and TLR5, whereas NL-20 expressed mainly TLR3 and HNECs expressed TLR2-5. In Detroit-562, Pam(3)CSK(4), poly(I:C) and flagellin, ligands for TLR2, TLR3 and TLR5, respectively, induced an up-regulation of intercellular adhesion molecule 1 (ICAM-1), an increase in interleukin (IL)-6 and IL-8 secretion and a decrease in cell viability. Additionally, poly(I:C) affected IL-1beta production and the migratory behaviour of Detroit-562. NL-20 responded with a slight increase in IL-8 secretion upon poly(I:C) stimulation. Poly(I:C) induced a small increase in IL-1beta, IL-6 and IL-8 production in HNECs, while Pam(3)CSK(4) increased viability. The TLR signalling was transcription-dependent, but the pathways involved differed among TLRs as well as cells. In Detroit-562, TLR2 and TLR5 activation was mediated via c-jun N-terminal kinase (JNK)-, p38-, phosphatidylinositol 3-kinase (PI3K)- and nuclear factor (NF)-kappaB-related pathways, while TLR3 was dependent on NF-kappaB. In NL-20, TLR3 signalled via p38, and in HNECs, NF-kappaB, JNK and extracellular signal-regulated kinase (ERK) appeared to be involved. We found that TLR agonists induced a robust response in HNSCCs, characterized by generation of inflammation and cell death. A similar response was not seen in normal epithelial cells. Thus, the TLR system should be considered an important target in future antitumour immunotherapy.
authors.affiliation: Division of ENT Diseases, CLINTEC, Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Rydberg
authors.forename: Anne
authors.initials: A
authors.lastname: Månsson
authors.forename: Rolf
authors.initials: R
authors.lastname: Uddman
authors.forename: Kristian
authors.initials: K
authors.lastname: Riesbeck
authors.forename: Lars-Olaf
authors.initials: LO
authors.lastname: Cardell
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D005408:Flagellin / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007369:Interferon Inducers / Q000494:pharmacology; D015850:Interleukin-6 / Q000819:agonists / Q000378:metabolism; D016209:Interleukin-8 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000819:agonists* / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000819:agonists* / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D007369:Interferon Inducers; D015850:Interleukin-6; D016209:Interleukin-8; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D047428:Protein Kinase Inhibitors; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495346:TLR5 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051198:Toll-Like Receptor 5; D018799:Intercellular Adhesion Molecule-1; D005408:Flagellin; D011494:Protein Kinases; D011070:Poly I-C