![]() ![]() Agonist tolerance can be mediated by a variety of mechanisms, including induction of negative regulators of TLR-signaling pathways, as well as by regulation of expression of TLRs and their signaling components ( 10). Similar tolerogenic effects were reported with a wide range of agonist–TLR combinations ( 12, 13). This may help to avoid the pathology associated with uncontrolled inflammation ( 11). Endotoxin tolerance is a well-described phenomenon involving TLR4 modulation, whereby cells exposed to LPS become less responsive to a continued or repeated exposure to this agonist. Overactivation of TLR4 with LPS leads to an acute systemic disease known as endotoxic shock. Most studies of TLR modulation are based on post-TLR agonist activation, such as the modulation of TLR4 after exposure to its ligand, bacterial LPS. Indeed, most known regulatory mechanisms target TLR-signaling pathways and, thus, broadly inhibit multiple aspects of the inflammatory response or regulate epigenetic changes on the promoter regions of inflammatory genes ( 10). The TLR multicomponent inflammatory response must be tightly regulated to avoid tissue damage, chronic inflammation, and aberrant production of proinflammatory cytokines. This complex was reported to be deacetylated by histone deacetylases (HDACs), which leads to attenuation of NF-κB transcriptional activity ( 10). p65 becomes transcriptionally active when acetylated at lysine residues by both p300 and PCAF. Numerous studies highlighted the diverse posttranslational modifications that exist, such as phosphorylation, monomethylation, ubiquitination, and acetylation, for p65 to achieve its full biological activity ( 9). Of the five known NF-κB family members, the p65 subunit is the most well studied. Specificity of NF-κB–triggered gene expression is achieved by several posttranslational modifications. Translocation of p50 and p65 into the nucleus allows for proinflammatory gene induction of cytokines such as TNF-α and pro–IL-1β. Activation of IKK leads to the degradation of IκB, which normally maintains NF-κBp65 (p65)/NF-κBp50 (p50) heterodimers in an inactive state by sequestering them in the cytoplasm. This association promotes the recruitment of IRAK1 and IRAK4, which form a complex with TRAF6 to activate TAK1 and IKK. Upon activation, TLR9 associates with the adaptor protein MyD88. Although TLR9 signaling in hematopoietic cells was demonstrated to control infection of several DNA viruses, TLR9 is also expressed on epithelial cells, such as keratinocytes ( 6– 8). TLR9 detects unmethylated CpG motifs found in the genomic DNA from a variety of viruses, such as EBV, human papillomavirus type 16 (HPV16), and HSV-2 ( 1– 5). TLRs 3, 7, 8, and 9 were demonstrated to recognize different forms of microbial-derived nucleic acid. They play a key role in host defense during pathogen infection by regulating and linking the innate and adaptive immune responses. Pattern-recognition receptors, including TLRs, are responsible for sensing microbial infection and tissue damage. These results provide a framework for understanding the complex pathways involved in transcriptional regulation of TLR9, immune induction, and inflammation against viruses. Knockdown of HDAC3 blocked the transient suppression in which TLR9 function was restored. Engagement of the TLR9 receptor induced the recruitment of a suppressive complex, consisting of NF-κBp65 and HDAC3, to an NF-κB cis element on the TLR9 promoter. TLR9 transcriptional downregulation was dependent on TLR9 signaling and was not induced by TLR5 or other NF-κB activators, such as TNF-α. We demonstrate that infection of primary human epithelial cells, B cells, and plasmacytoid dendritic cells with dsDNA viruses induces a regulatory temporary negative-feedback loop that blocks TLR9 transcription and function. In this study, we examined the relationship between activation and the transcriptional regulation of TLR9. ![]() Because uncontrolled inflammation can be life threatening, TLR regulation is important however, few studies have identified the signaling pathways that contribute to the modulation of TLR expression. The stimulation of TLRs by pathogen-derived molecules leads to the production of proinflammatory cytokines. ![]()
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