Toll‐like receptor agonists induce inflammation and cell death in a model of head and neck squamous cell carcinomas

• Published in: Immunology Vol. 128; no. 1pt2; pp. e600 - e611
• Main Authors: Rydberg, Camilla, Månsson, Anne, Uddman, Rolf, Riesbeck, Kristian, Cardell, Lars‐Olaf
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2009; Blackwell Science Inc
• Subjects: apoptosis; Basic Medicine; cancer; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - immunology; Cell Survival - drug effects; Cell Survival - immunology; Epithelial Cells - drug effects; Epithelial Cells - immunology; Flagellin - pharmacology; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - pathology; Humans; Immunologi inom det medicinska området; Immunology in the medical area; inflammation; Inflammation - immunology; Intercellular Adhesion Molecule-1 - drug effects; Intercellular Adhesion Molecule-1 - immunology; Intercellular Adhesion Molecule-1 - metabolism; Interferon Inducers - pharmacology; Interleukin-6 - agonists; Interleukin-6 - metabolism; Interleukin-8 - agonists; Interleukin-8 - immunology; Interleukin-8 - metabolism; Lipopeptides - pharmacology; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Original; Poly I-C - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein Kinases - drug effects; Protein Kinases - immunology; Protein Kinases - metabolism; receptors; signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; Toll-like; Toll-Like Receptor 2 - agonists; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 3 - agonists; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 5 - agonists; Toll-Like Receptor 5 - metabolism; Toll‐like receptors
• ISSN: 0019-2805; 1365-2567; 1365-2567
• DOI: 10.1111/j.1365-2567.2008.03041.x

Summary 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, Pam3CSK4, 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‐1β 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‐1β, IL‐6 and IL‐8 production in HNECs, while Pam3CSK4 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)‐κB‐related pathways, while TLR3 was dependent on NF‐κB. In NL‐20, TLR3 signalled via p38, and in HNECs, NF‐κB, 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.