757 publications from this institution
Toll-like receptors (TLRs) in the host recognize conserved microbial products and defend against pathogenic attack by initiating an immune response via signalling pathways that lead to an increase in immune and inflammatory gene expression. TLR signalling must be stringently regulated in order to ensure sufficient clearance of pathogens and a timely return to homeostasis after infection. MicroRNAs (miRNAs) are a newly discovered class of gene regulators which bind to the 3′ untranslated region of target mRNA and direct their post-transcriptional repression. They are global regulators potentially controlling up to 30% of the human genome. Several miRNAs have been shown to be up-regulated in response to TLR ligands, and many directly target components of the TLR signalling system, revealing a whole extra level of control of TLR signalling which is being extensively researched. The dysregulation of miRNAs may be involved in many inflammatory diseases and cancers and thus merits further investigation. In this review, we focus in on a trio of miRNA which have proven to be key in many immune and inflammatory pathways; miR-155, miR-21 and miR-146.
The transcription factor NF-κB is a central mediator of altered gene expression during inflammation, and is implicated in a number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the activation of NF-κB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-κB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-κB. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-κB were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-κBα (inhibitory protein that dissociates from NF-κB), due to inhibition of I-κB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase, because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580 reversed the inhibitory effect of vitamin C on IKK activity, I-κBα phosphorylation, and NF-κB activation. The results identify p38 as an intracellular target for high dose vitamin C.
