Biased signalling is an essential feature of TLR4 in glioma cells
A distinct feature of the Toll-like receptor 4 (TLR4) is its ability to trigger both MyD88-dependent and MyD88-independent signalling, culminating in activation of pro-inflammatory NF-κB and/or the antiviral IRF3. Although TLR4 agonists (lipopolysaccharides; LPSs) derived from different bacterial sp...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
December 2016
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| In: |
Biochimica et biophysica acta. Molecular cell research
Year: 2016, Volume: 1863, Issue: 12, Pages: 3084-3095 |
| ISSN: | 1879-2596 |
| DOI: | 10.1016/j.bbamcr.2016.09.016 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1016/j.bbamcr.2016.09.016 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0167488916302452 
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| Author Notes: | Marie-Theres Zeuner, Carmen L Krüger, Katharina Volk, Karen Bieback, Graeme S Cottrell, Mike Heilemann, Darius Widera |
| Summary: | A distinct feature of the Toll-like receptor 4 (TLR4) is its ability to trigger both MyD88-dependent and MyD88-independent signalling, culminating in activation of pro-inflammatory NF-κB and/or the antiviral IRF3. Although TLR4 agonists (lipopolysaccharides; LPSs) derived from different bacterial species have different endotoxic activity, the impact of LPS chemotype on the downstream signalling is not fully understood. Notably, different TLR4 agonists exhibit anti-tumoural activity in animal models of glioma, but the underlying molecular mechanisms are largely unknown. Thus, we investigated the impact of LPS chemotype on the signalling events in the human glioma cell line U251. We found that LPS of Escherichia coli origin (LPSEC) leads to NF-κB-biased downstream signalling compared to Salmonella minnesota-derived LPS (LPSSM). Exposure of U251 cells to LPSEC resulted in faster nuclear translocation of the NF-κB subunit p65, higher NF-κB-activity and expression of its targets genes, and higher amount of secreted IL-6 compared to LPSSM. Using super-resolution microscopy we showed that the biased agonism of TLR4 in glioma cells is neither a result of differential regulation of receptor density nor of formation of higher order oligomers. Consistent with previous reports, LPSEC-mediated NF-κB activation led to significantly increased U251 proliferation, whereas LPSSM-induced IRF3 activity negatively influenced their invasiveness. Finally, treatment with methyl-β-cyclodextrin (MCD) selectively increased LPSSM-induced nuclear translocation of p65 and NF-κB activity without affecting IRF3. Our data may explain how TLR4 agonists differently affect glioma cell proliferation and migration. |
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| Item Description: | Gesehen am 11.04.2019 Available online 23 September 2016 |
| Physical Description: | Online Resource |
| ISSN: | 1879-2596 |
| DOI: | 10.1016/j.bbamcr.2016.09.016 |