The genetic determinants of inflammation
Central to immune responses is the recognition of pathogens through specialised sensors known as Toll-like receptors (TLRs). TLRs get activated through binding of different bacterial components such as glycolipids, lipopolysaccharides (LPS) or RNA. This induces a downstream signalling of events which culminates in expression of inflammatory genes. Despite the importance of TLR activation, uncontrolled or prolonged activation can lead to devastating consequences such as inflammatory diseases. Different negative regulators prohibit such sustained receptor activation and tightly regulate the process of TLR activation. This phenomenon is known as TLR tolerance and was the subject of investigation of the EU-funded 'Investigation of the regulation of toll-like receptor mediated transcription' (TLR TOLERANCE) project. Emerging evidence indicates that TLR tolerance is a gene-specific phenomenon with only certain genes being sensitive to LPS tolerance. The selective inactivation of inflammatory but not antimicrobial genes ensures that the host can build up its immunity against microbes whilst avoiding the emergence of inflammatory disease. Researchers on the TLR TOLERANCE project investigated the mechanism underlying this selective gene targeting. They found that B cell leukaemia-3 (bcl3) inactivated the transcription factor called nuclear factor (NF)-kb to induce tolerance. This transcription factor is normally activated by LPS. Additionally, scientists performed bioinformatics analysis of many LPS target genes and identified that NF-kb can only bind on genes that are LPS tolerised. By delineating the mechanisms of NF-kb inactivation, they were able to elucidate its interaction with bcl3 and precisely identify the binding sites. These findings led to the design of peptides with potential therapeutic utility that were able to reduce the inflammatory cytokine IL-23 in cells. Overall, the work by the TLR TOLERANCE project sets the basis for unravelling the transcriptional regulation of inflammation. Further investigation of the modulating activity of the generated peptides could lead to novel therapeutic interventions for inflammatory diseases.
Keywords
Inflammatory diseases, Toll-like receptor, lipopolysaccharide, signalling, TLR tolerance, B cell leukaemia-3, NF-kb, peptide
