NF-κB in the regulation of epithelial homeostasis and inflammation

Abstract

The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

Differential Responses of Normal Human Melanocytes to Intra- and Extracellular dsRNA

“…Both TBK1 and TAK1 activate NFkB and lead to downstream transcription. NFkB was reported to participate in the transcription regulation of type I interferon as well as proinflammatory cytokine genes (Wullaert et al, 2011). Consistent with previous findings, we showed that induction of cytokines by poly(I:C) was significantly suppressed by inhibition of NFkB activation indicating that NFkB is ubiquitously employed in the regulation of poly(I:C)-induced cytokine expression in normal human melanocytes.…”

Neuroprotective roles of the P2Y2 receptor

“…Activation of the P2X7R in microglia promotes the release of IL-1β, TNF-α, and ATP [16,75,105,[154][155][156], suggesting a mechanism whereby the P2X7R regulates functional P2Y 2 R expression in neurons and other cells. The finding that P2Y 2 R expression under proinflammatory conditions is regulated by NF-κB binding to the P2Y 2 R promoter [104] is consistent with the established role of NF-κB activation in the induction of inflammation [157].…”

Effect of feed supplementation with live yeast on the intestinal transcriptome profile of weaning pigs orally challenged with Escherichia coli F4

“…It could be hypothesized that preliminary treatment for 1 week could have supported the increase in immune-competent cell production as already evidenced during the supply of probiotics in infected pigs (Rieger et al, 2015). The upregulation of genes involved in the differentiation and proliferation of T and B lymphocytes, after the preventive supply of the yeast, indicated a stronger stimulation of the gut mucosa and the activation of the canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathways (Wullaert et al, 2011). On the other hand, the PR diet, like AB, downregulated the CCL20 chemokine, preventing the effect observed in a variety of inflammatory disorders (Sibartie et al, 2009).…”